Estrogen receptor modulators

ABSTRACT

Compounds of Formula (I) are estrogen receptor alpha modulators, where the variables in Formula (I) are described in the disclosure. Such compounds, as well as pharmaceutically acceptable salts and compositions thereof, are useful for treating diseases or conditions that are estrogen receptor alpha dependent and/or estrogen receptor alpha mediated, including conditions characterized by excessive cellular proliferation, such as breast cancer.

INCORPORATION BY REFERENCE TO ANY PRIORITY APPLICATIONS

This application is a divisional of U.S. application Ser. No.16/086,434, filed Sep. 19, 2018, which is a national stage filing under§ 371 of PCT Application No. PCT/US2017/024809, filed Mar. 29, 2017,which claims priority to U.S. Provisional Application Ser. No.62/317,254, filed September Apr. 1, 2016. All of the foregoing arehereby incorporated herein by references in their entireties.

FIELD

The present application relates to compounds that are estrogen receptoralpha modulators and methods of using them to treat conditionscharacterized by excessive cellular proliferation, such as cancer.

DESCRIPTION

Many cancer cells express estrogen receptors (ERs) and have growthcharacteristics that are modulated by estrogen. A number of breastcancer drug therapies have been developed that target ERs. In many casesthe drugs are selective estrogen receptor modulators (SERMs) that haveagonistic and/or antagonistic effects on ERs. For example, fulvestrantis a drug that is used for the treatment of metastatic breast cancer. Ithas antagonistic effects on ER-alpha and is considered a selectiveestrogen receptor alpha degrader (SERD). Fulvestrant has the followingchemical structure:

A compound known as RAD1901 has also been reported to be a SERD. SeeGarner, F. et al., “RAD1901: a novel, orally bioavailable selectiveestrogen receptor degrader that demonstrates antitumor activity inbreast cancer xenograft models” Anti-Cancer Drugs 26(9), 948-956 (2015).RAD1901 has the following chemical structure:

Other reported SERDs include the compounds known as AZD9496 andGDC-0810. See De Savi, C. et al., “Optimization of a Novel Binding Motifto(E)-3-(3,5-Difluoro-4-((1R,3R)2-(2-fluoro-2-methylpropyl)-3-methyl-2,3,4,9-tetrahydro-1H-pyrido[3,4b]indol-1-yl)phenyl)acrylicAcid (AZD9496), a Potent and Orally Bioavailable Selective EstrogenReceptor Downregulator and Antagonist”, J. Med. Chem. 58, 8128-8140(2015) (“De Savi”) and Lai, A. et al., “Identification of GDC-0810(ARN-810), an Orally Bioavailable Selective Estrogen Receptor Degrader(SERD) that Demonstrates Robust Activity in Tamoxifen-Resistant BreastCancer Xenografts”, J. Med. Chem. 58, 4888-4904 (2015). AZD9496 andGDC-0810 have the following chemical structures:

Other reported SERDs include those disclosed in WO 2008/002490; WO2011/156518; WO 2013/090829; WO 2013/090836; WO 2013/142266; WO2014/151899; WO 2014/191726; WO 2015/082990; and US 2014/00235660.

At this time the only SERD approved for the treatment of breast cancerin the United States is fulvestrant. However, the clinical efficacy offulvestrant is limited and fulvestrant has to be dosed via intramuscularinjection. A number of orally dosed SERDs are currently in clinicaldevelopment (e.g. ARN-810 (GDC-0810), AZD9496, SRN-927, RAD1901,LSZ102), but at this time no oral SERD has been approved for thetreatment of breast cancer in the United States (see De Savi, C. et al.publication referenced above). Thus, there remains a long-felt need forwell tolerated orally dosed SERDs or SERMs that are useful in the studyand the treatment of proliferative disorders, such as breast cancer,that have growth characteristics that are modulated by estrogen.

SUMMARY

An embodiment provides a compound of Formula (I), or a pharmaceuticallyacceptable salt thereof, having the structure below.

In an embodiment, X¹, Y¹ and Z¹ are each independently C or N, with thefirst proviso that at least one of X¹, Y¹ and Z¹ is N; with the secondproviso that each of X¹, Y¹ and Z¹ is uncharged; with third proviso thattwo of the dotted lines indicate double bonds; and with the fourthproviso that the valencies of X¹, Y¹ and Z¹ can be each independentlysatisfied by attachment to a substituent selected from H and R¹².

In an embodiment, A¹ is selected from the group consisting of anoptionally substituted cycloalkyl, an optionally substituted aryl, anoptionally substituted heteroaryl and an optionally substitutedheterocyclyl. In an embodiment, X² is O, NH or S.

In an embodiment, R¹ is selected from the group consisting of anoptionally substituted C₁₋₆ alkyl, an optionally substituted cycloalkyl,an optionally substituted cycloalkenyl, an optionally substituted aryl,an optionally substituted heteroaryl, an optionally substitutedheterocyclyl, an optionally substituted cycloalkyl(C₁₋₆ alkyl), anoptionally substituted cycloalkenyl(C₁₋₆ alkyl), an optionallysubstituted aryl(C₁₋₆ alkyl), an optionally substituted heteroaryl(C₁₋₆alkyl) and an optionally substituted heterocyclyl(C₁₋₆ alkyl).

In an embodiment, R² and R³ are each independently selected from thegroup consisting of hydrogen, halogen, an optionally substituted C₁₋₆alkyl and an optionally substituted C₁₋₆ haloalkyl; or R² and R³together with the carbon to which R² and R³ are attached form anoptionally substituted cycloalkyl, an optionally substitutedcycloalkenyl or an optionally substituted heterocyclyl.

In an embodiment, R⁴ and R⁵ are each independently selected from thegroup consisting of hydrogen, halogen, an optionally substituted C₁₋₆alkyl and an optionally substituted C₁₋₆ haloalkyl; or R⁴ and R⁵together with the carbon to which R⁴ and R⁵ are attached form anoptionally substituted cycloalkyl, an optionally substitutedcycloalkenyl or an optionally substituted heterocyclyl.

In an embodiment, R⁶, R⁷, R⁸ and R⁹ are each independently selected fromthe group consisting of hydrogen, halogen, hydroxy, an optionallysubstituted alkyl, an optionally substituted alkoxy, an optionallysubstituted haloalkyl, an optionally substituted mono-substituted amine,and an optionally substituted di-substituted amine.

In an embodiment, R¹⁰ is hydrogen, halogen, an optionally substitutedalkyl, or an optionally substituted cycloalkyl.

In an embodiment, R¹¹ is hydrogen or an optionally substituted C₁₋₆alkyl.

In an embodiment, R¹² is hydrogen, halogen, an optionally substitutedC₁₋₃ alkyl, an optionally substituted C₁₋₃ haloalkyl or an optionallysubstituted C₁₋₃ alkoxy.

In an embodiment, provided that when R¹¹ is hydrogen or methyl, X¹ isNH, Y¹ and Z¹ are each C, X² is O, A¹ is a phenyl, 2-fluorophenyl, or2,6-difluorophenyl, both R² and R³ are methyl or one of R² and R³ ishydrogen and the other of R² and R³ is methyl, and R⁴, R⁵, R⁶, R⁷, R⁸,R⁹ and R¹⁰ are each hydrogen, then R¹ cannot be 2-hydroxyethyl,2-methylpropyl, 2-fluoro-2-methylpropyl, 3-fluoro-2-methylpropyl,3-hydroxy-2-methylpropyl or 2-fluoro-3-hydroxy-2-methylpropyl.

In an embodiment, any one or more of each of R², R³, R⁴, R⁵, R⁶, R⁷, R⁸,R⁹ and R¹⁰ is hydrogen.

An embodiment provides a pharmaceutical composition comprising aneffective amount of the compound of Formula (I), or a pharmaceuticallyacceptable salt thereof, and a pharmaceutically acceptable carrier,diluent, excipient or combination thereof.

An embodiment provides a method of treatment, comprising identifying asubject that is in need of treatment for a disease or condition that isestrogen receptor alpha dependent and/or estrogen receptor alphamediated; and administering to said subject an effective amount of acompound of Formula (I), or a pharmaceutically acceptable salt thereof,or a pharmaceutical composition comprising a compound of Formula (I). Inan embodiment, the disease or condition is selected from the groupconsisting of a breast cancer and a gynecological cancer. In anembodiment, the disease or condition is selected from the groupconsisting of breast cancer, endometrial cancer, ovarian cancer, andcervical cancer.

An embodiment provides a compound of Formula (I), or a pharmaceuticallyacceptable salt thereof, or a pharmaceutical composition comprising acompound of Formula (I), for use in the treatment of a disease orcondition that is estrogen receptor alpha dependent and/or estrogenreceptor alpha mediated.

These and other embodiments are described in greater detail below.

DRAWINGS

FIG. 1 illustrates General Scheme 1 for preparing compounds of theFormula (I).

FIG. 2 illustrates a method of making Compound 11A.

DETAILED DESCRIPTION Definitions

Unless defined otherwise, all technical and scientific terms used hereinhave the same meaning as is commonly understood by one of ordinary skillin the art. All patents, applications, published applications and otherpublications referenced herein are incorporated by reference in theirentirety unless stated otherwise. In the event that there are aplurality of definitions for a term herein, those in this sectionprevail unless stated otherwise.

Whenever a group is described as being “optionally substituted” thatgroup may be unsubstituted or substituted with one or more of theindicated substituents. Likewise, when a group is described as being“unsubstituted or substituted” if substituted, the substituent(s) may beselected from one or more the indicated substituents. If no substituentsare indicated, it is meant that the indicated “optionally substituted”or “substituted” group may be substituted with one or more group(s)individually and independently selected from alkyl, alkenyl, alkynyl,cycloalkyl, cycloalkenyl, cycloalkynyl, aryl, heteroaryl, heterocyclyl,aryl(alkyl), cycloalkyl(alkyl), heteroaryl(alkyl), heterocyclyl(alkyl),hydroxy, alkoxy, acyl, cyano, halogen, thiocarbonyl, O-carbamyl,N-carbamyl, O-thiocarbamyl, N-thiocarbamyl, C-amido, N-amido,S-sulfonamido, N-sulfonamido, C-carboxy, O-carboxy, nitro, sulfenyl,sulfinyl, sulfonyl, haloalkyl, haloalkoxy, an amino, a mono-substitutedamino group and a di-substituted amino group.

As used herein, “C_(a) to C_(b)” in which “a” and “b” are integers referto the number of carbon atoms in a group. The indicated group cancontain from “a” to “b”, inclusive, carbon atoms. Thus, for example, a“C₁ to C₄ alkyl” group refers to all alkyl groups having from 1 to 4carbons, that is, CH₃—, CH₃CH₂—, CH₃CH₂CH₂—, (CH₃)₂CH—, CH₃CH₂CH₂CH₂—,CH₃CH₂CH(CH₃)— and (CH₃)₃C—. If no “a” and “b” are designated, thebroadest range described in these definitions is to be assumed.

If two “R” groups are described as being “taken together” the R groupsand the atoms they are attached to can form a cycloalkyl, cycloalkenyl,aryl, heteroaryl or heterocycle. For example, without limitation, ifR^(a) and R^(b) of an NR^(a) R^(b) group are indicated to be “takentogether,” it means that they are covalently bonded to one another toform a ring:

As used herein, the term “alkyl” refers to a fully saturated aliphatichydrocarbon group. The alkyl moiety may be branched or straight chain.Examples of branched alkyl groups include, but are not limited to,iso-propyl, sec-butyl, t-butyl and the like. Examples of straight chainalkyl groups include, but are not limited to, methyl, ethyl, n-propyl,n-butyl, n-pentyl, n-hexyl, n-heptyl and the like. The alkyl group mayhave 1 to 30 carbon atoms (whenever it appears herein, a numerical rangesuch as “1 to 30” refers to each integer in the given range; e.g., “1 to30 carbon atoms” means that the alkyl group may consist of 1 carbonatom, 2 carbon atoms, 3 carbon atoms, etc., up to and including 30carbon atoms, although the present definition also covers the occurrenceof the term “alkyl” where no numerical range is designated). The alkylgroup may also be a medium size alkyl having 1 to 12 carbon atoms. Thealkyl group could also be a lower alkyl having 1 to 6 carbon atoms. Analkyl group may be substituted or unsubstituted.

The term “alkenyl” used herein refers to a monovalent straight orbranched chain radical of from two to twenty carbon atoms containing acarbon double bond(s) including, but not limited to, 1-propenyl,2-propenyl, 2-methyl-1-propenyl, 1-butenyl, 2-butenyl and the like. Analkenyl group may be unsubstituted or substituted.

The term “alkynyl” used herein refers to a monovalent straight orbranched chain radical of from two to twenty carbon atoms containing acarbon triple bond(s) including, but not limited to, 1-propynyl,1-butynyl, 2-butynyl and the like. An alkynyl group may be unsubstitutedor substituted.

As used herein, “cycloalkyl” refers to a completely saturated (no doubleor triple bonds) mono- or multi-cyclic hydrocarbon ring system. Whencomposed of two or more rings, the rings may be joined together in afused, bridged or spiro fashion. As used herein, the term “fused” refersto two rings which have two atoms and one bond in common. As usedherein, the term “bridged cycloalkyl” refers to compounds wherein thecycloalkyl contains a linkage of one or more atoms connectingnon-adjacent atoms. As used herein, the term “spiro” refers to two ringswhich have one atom in common and the two rings are not linked by abridge. Cycloalkyl groups can contain 3 to 30 atoms in the ring(s), 3 to20 atoms in the ring(s), 3 to 10 atoms in the ring(s), 3 to 8 atoms inthe ring(s) or 3 to 6 atoms in the ring(s). A cycloalkyl group may beunsubstituted or substituted. Typical mono-cycloalkyl groups include,but are in no way limited to, cyclopropyl, cyclobutyl, cyclopentyl,cyclohexyl, cycloheptyl, and cyclooctyl. Examples of fused cycloalkylgroups are decahydronaphthalenyl, dodecahydro-1H-phenalenyl andtetradecahydroanthracenyl; examples of bridged cycloalkyl groups arebicyclo[1.1.1]pentyl, adamantanyl, and norbornanyl; and examples ofspiro cycloalkyl groups include spiro[3.3]heptane and spiro[4.5]decane.

As used herein, “cycloalkenyl” refers to a mono- or multi-cyclichydrocarbon ring system that contains one or more double bonds in atleast one ring; although, if there is more than one, the double bondscannot form a fully delocalized pi-electron system throughout all therings (otherwise the group would be “aryl,” as defined herein).Cycloalkenyl groups can contain 3 to 10 atoms in the ring(s) or 3 to 8atoms in the ring(s). When composed of two or more rings, the rings maybe connected together in a fused, bridged or spiro fashion. Acycloalkenyl group may be unsubstituted or substituted.

As used herein, “cycloalkynyl” refers to a mono- or multi-cyclichydrocarbon ring system that contains one or more triple bonds in atleast one ring. If there is more than one triple bond, the triple bondscannot form a fully delocalized pi-electron system throughout all therings. Cycloalkynyl groups can contain 6 to 10 atoms in the ring(s) or 6to 8 atoms in the ring(s). When composed of two or more rings, the ringsmay be joined together in a fused, bridged or spiro fashion. Acycloalkynyl group may be unsubstituted or substituted.

As used herein, “aryl” refers to a carbocyclic (all carbon) monocyclicor multicyclic aromatic ring system (including fused ring systems wheretwo carbocyclic rings share a chemical bond) that has a fullydelocalized pi-electron system throughout all the rings. The number ofcarbon atoms in an aryl group can vary. For example, the aryl group canbe a C₆-C₁₄ aryl group, a C₆-C₁₀ aryl group, or a C₆ aryl group.Examples of aryl groups include, but are not limited to, benzene,naphthalene and azulene. An aryl group may be substituted orunsubstituted.

As used herein, “heteroaryl” refers to a monocyclic or multicyclicaromatic ring system (a ring system with fully delocalized pi-electronsystem) that contain(s) one or more heteroatoms (for example, 1, 2 or 3heteroatoms), that is, an element other than carbon, including but notlimited to, nitrogen, oxygen and sulfur. The number of atoms in thering(s) of a heteroaryl group can vary. For example, the heteroarylgroup can contain 4 to 14 atoms in the ring(s), 5 to 10 atoms in thering(s) or 5 to 6 atoms in the ring(s). Furthermore, the term“heteroaryl” includes fused ring systems where two rings, such as atleast one aryl ring and at least one heteroaryl ring, or at least twoheteroaryl rings, share at least one chemical bond. Examples ofheteroaryl rings include, but are not limited to, furan, furazan,thiophene, benzothiophene, phthalazine, pyrrole, oxazole, benzoxazole,1,2,3-oxadiazole, 1,2,4-oxadiazole, thiazole, 1,2,3-thiadiazole,1,2,4-thiadiazole, benzothiazole, imidazole, benzimidazole, indole,indazole, pyrazole, benzopyrazole, isoxazole, benzoisoxazole,isothiazole, triazole, benzotriazole, thiadiazole, tetrazole, pyridine,pyridazine, pyrimidine, pyrazine, purine, pteridine, quinoline,isoquinoline, quinazoline, quinoxaline, cinnoline and triazine. Aheteroaryl group may be substituted or unsubstituted.

As used herein, “heterocyclyl” or “heteroalicyclyl” refers to three-,four-, five-, six-, seven-, eight-, nine-, ten-, up to 18-memberedmonocyclic, bicyclic and tricyclic ring system wherein carbon atomstogether with from 1 to 5 heteroatoms constitute said ring system. Aheterocycle may optionally contain one or more unsaturated bondssituated in such a way, however, that a fully delocalized pi-electronsystem does not occur throughout all the rings. The heteroatom(s) is anelement other than carbon including, but not limited to, oxygen, sulfurand nitrogen. A heterocycle may further contain one or more carbonyl orthiocarbonyl functionalities, so as to make the definition includeoxo-systems and thio-systems such as lactams, lactones, cyclic imides,cyclic thioimides and cyclic carbamates. When composed of two or morerings, the rings may be joined together in a fused, bridged or spirofashion. As used herein, the term “fused” refers to two rings which havetwo atoms and one bond in common. As used herein, the term “bridgedheterocyclyl” or “bridged heteroalicyclyl” refers to compounds whereinthe heterocyclyl or heteroalicyclyl contains a linkage of one or moreatoms connecting non-adjacent atoms. As used herein, the term “spiro”refers to two rings which have one atom in common and the two rings arenot linked by a bridge. Heterocyclyl and heteroalicyclyl groups cancontain 3 to 30 atoms in the ring(s), 3 to 20 atoms in the ring(s), 3 to10 atoms in the ring(s), 3 to 8 atoms in the ring(s) or 3 to 6 atoms inthe ring(s). Additionally, any nitrogens in a heteroalicyclic may bequaternized. Heterocyclyl or heteroalicyclic groups may be unsubstitutedor substituted. Examples of such “heterocyclyl” or “heteroalicyclyl”groups include but are not limited to, 1,3-dioxin, 1,3-dioxane,1,4-dioxane, 1,2-dioxolane, 1,3-dioxolane, 1,4-dioxolane, 1,3-oxathiane,1,4-oxathiin, 1,3-oxathiolane, 1,3-dithiole, 1,3-dithiolane,1,4-oxathiane, tetrahydro-1,4-thiazine, 2H-1,2-oxazine, maleimide,succinimide, barbituric acid, thiobarbituric acid, dioxopiperazine,hydantoin, dihydrouracil, trioxane, hexahydro-1,3,5-triazine,imidazoline, imidazolidine, isoxazoline, isoxazolidine, oxazoline,oxazolidine, oxazolidinone, thiazoline, thiazolidine, morpholine,oxirane, piperidine N-Oxide, piperidine, piperazine, pyrrolidine,azepane, pyrrolidone, pyrrolidione, 4-piperidone, pyrazoline,pyrazolidine, 2-oxopyrrolidine, tetrahydropyran, 4H-pyran,tetrahydrothiopyran, thiamorpholine, thiamorpholine sulfoxide,thiamorpholine sulfone and their benzo-fused analogs (e.g.,benzimidazolidinone, tetrahydroquinoline and/or3,4-methylenedioxyphenyl). Examples of spiro heterocyclyl groups include2-azaspiro[3.3]heptane, 2-oxaspiro[3.3]heptane,2-oxa-6-azaspiro[3.3]heptane, 2,6-diazaspiro[3.3]heptane,2-oxaspiro[3.4]octane and 2-azaspiro[3.4]octane.

As used herein, “aralkyl” and “aryl(alkyl)” refer to an aryl groupconnected, as a substituent, via a lower alkylene group. The loweralkylene and aryl group of an aralkyl may be substituted orunsubstituted. Examples include but are not limited to benzyl,2-phenylalkyl, 3-phenylalkyl and naphthylalkyl.

As used herein, “heteroaralkyl” and “heteroaryl(alkyl)” refer to aheteroaryl group connected, as a substituent, via a lower alkylenegroup. The lower alkylene and heteroaryl group of heteroaralkyl may besubstituted or unsubstituted. Examples include but are not limited to2-thienylalkyl, 3-thienylalkyl, furylalkyl, thienylalkyl, pyrrolylalkyl,pyridylalkyl, isoxazolylalkyl and imidazolylalkyl and their benzo-fusedanalogs.

A “heteroalicyclyl(alkyl)” and “heterocyclyl(alkyl)” refer to aheterocyclic or a heteroalicyclylic group connected, as a substituent,via a lower alkylene group. The lower alkylene and heterocyclyl of a(heteroalicyclyl)alkyl may be substituted or unsubstituted. Examplesinclude but are not limited tetrahydro-2H-pyran-4-yl(methyl),piperidin-4-yl(ethyl), piperidin-4-yl(propyl),tetrahydro-2H-thiopyran-4-yl(methyl) and 1,3-thiazinan-4-yl(methyl).

As used herein, “lower alkylene groups” are straight-chained—CH₂-tethering groups, forming bonds to connect molecular fragments viatheir terminal carbon atoms. Examples include but are not limited tomethylene (—CH₂—), ethylene (—CH₂CH₂—), propylene (—CH₂CH₂CH₂—) andbutylene (—CH₂CH₂CH₂CH₂—). A lower alkylene group can be substituted byreplacing one or more hydrogen of the lower alkylene group and/or bysubstituting both hydrogens on the same carbon with a cycloalkyl group(e.g.,

As used herein, the term “hydroxy” refers to a —OH group.

As used herein, “alkoxy” refers to the Formula —OR wherein R is analkyl, an alkenyl, an alkynyl, a cycloalkyl, a cycloalkenyl, aryl,heteroaryl, heterocyclyl, cycloalkyl(alkyl), aryl(alkyl),heteroaryl(alkyl) or heterocyclyl(alkyl) is defined herein. Anon-limiting list of alkoxys are methoxy, ethoxy, n-propoxy,1-methylethoxy (isopropoxy), n-butoxy, iso-butoxy, sec-butoxy,tert-butoxy, phenoxy and benzoxy. An alkoxy may be substituted orunsubstituted.

As used herein, “acyl” refers to a hydrogen, alkyl, alkenyl, alkynyl,aryl, heteroaryl, heterocyclyl, aryl(alkyl), heteroaryl(alkyl) andheterocyclyl(alkyl) connected, as substituents, via a carbonyl group.Examples include formyl, acetyl, propanoyl, benzoyl and acryl. An acylmay be substituted or unsubstituted.

A “cyano” group refers to a “—CN” group.

The term “halogen atom” or “halogen” as used herein, means any one ofthe radio-stable atoms of column 7 of the Periodic Table of theElements, such as, fluorine, chlorine, bromine and iodine.

A “thiocarbonyl” group refers to a “—C(═S)R” group in which R can be thesame as defined with respect to O-carboxy. A thiocarbonyl may besubstituted or unsubstituted.

An “O-carbamyl” group refers to a “—OC(═O)N(R_(A)R_(B))” group in whichR_(A) and R_(B) can be independently hydrogen, an alkyl, an alkenyl, analkynyl, a cycloalkyl, a cycloalkenyl, aryl, heteroaryl, heterocyclyl,cycloalkyl(alkyl), aryl(alkyl), heteroaryl(alkyl) orheterocyclyl(alkyl). An O-carbamyl may be substituted or unsubstituted.

An “N-carbamyl” group refers to an “ROC(═O)N(R_(A))—” group in which Rand R_(A) can be independently hydrogen, an alkyl, an alkenyl, analkynyl, a cycloalkyl, a cycloalkenyl, aryl, heteroaryl, heterocyclyl,cycloalkyl(alkyl), aryl(alkyl), heteroaryl(alkyl) orheterocyclyl(alkyl). An N-carbamyl may be substituted or unsubstituted.

An “O-thiocarbamyl” group refers to a “—OC(═S)—N(R_(A)R_(B))” group inwhich R_(A) and R_(B) can be independently hydrogen, an alkyl, analkenyl, an alkynyl, a cycloalkyl, a cycloalkenyl, aryl, heteroaryl,heterocyclyl, cycloalkyl(alkyl), aryl(alkyl), heteroaryl(alkyl) orheterocyclyl(alkyl). An O-thiocarbamyl may be substituted orunsubstituted.

An “N-thiocarbamyl” group refers to an “ROC(═S)N(R_(A))—” group in whichR and R_(A) can be independently hydrogen, an alkyl, an alkenyl, analkynyl, a cycloalkyl, a cycloalkenyl, aryl, heteroaryl, heterocyclyl,cycloalkyl(alkyl), aryl(alkyl), heteroaryl(alkyl) orheterocyclyl(alkyl). An N-thiocarbamyl may be substituted orunsubstituted.

A “C-amido” group refers to a “—C(═O)N(R_(A)R_(B))” group in which R_(A)and R_(B) can be independently hydrogen, an alkyl, an alkenyl, analkynyl, a cycloalkyl, a cycloalkenyl, aryl, heteroaryl, heterocyclyl,cycloalkyl(alkyl), aryl(alkyl), heteroaryl(alkyl) orheterocyclyl(alkyl). A C-amido may be substituted or unsubstituted.

An “N-amido” group refers to a “RC(═O)N(R_(A))—” group in which R andR_(A) can be independently hydrogen, an alkyl, an alkenyl, an alkynyl, acycloalkyl, a cycloalkenyl, aryl, heteroaryl, heterocyclyl,cycloalkyl(alkyl), aryl(alkyl), heteroaryl(alkyl) orheterocyclyl(alkyl). An N-amido may be substituted or unsubstituted.

An “S-sulfonamido” group refers to a “—SO₂N(R_(A)R_(B))” group in whichR_(A) and R_(B) can be independently hydrogen, an alkyl, an alkenyl, analkynyl, a cycloalkyl, a cycloalkenyl, aryl, heteroaryl, heterocyclyl,cycloalkyl(alkyl), aryl(alkyl), heteroaryl(alkyl) orheterocyclyl(alkyl). An S-sulfonamido may be substituted orunsubstituted.

An “N-sulfonamido” group refers to a “RSO₂N(R_(A))—” group in which Rand R_(A) can be independently hydrogen, an alkyl, an alkenyl, analkynyl, a cycloalkyl, a cycloalkenyl, aryl, heteroaryl, heterocyclyl,cycloalkyl(alkyl), aryl(alkyl), heteroaryl(alkyl) orheterocyclyl(alkyl). An N-sulfonamido may be substituted orunsubstituted.

An “O-carboxy” group refers to a “RC(═O)O—” group in which R can behydrogen, an alkyl, an alkenyl, an alkynyl, a cycloalkyl, acycloalkenyl, aryl, heteroaryl, heterocyclyl, cycloalkyl(alkyl),aryl(alkyl), heteroaryl(alkyl) or heterocyclyl(alkyl), as definedherein. An O-carboxy may be substituted or unsubstituted.

The terms “ester” and “C-carboxy” refer to a “—C(═O)OR” group in which Rcan be the same as defined with respect to O-carboxy. An ester andC-carboxy may be substituted or unsubstituted.

A “nitro” group refers to an “—NO₂” group.

A “sulfenyl” group refers to an “—SR” group in which R can be hydrogen,an alkyl, an alkenyl, an alkynyl, a cycloalkyl, a cycloalkenyl, aryl,heteroaryl, heterocyclyl, cycloalkyl(alkyl), aryl(alkyl),heteroaryl(alkyl) or heterocyclyl(alkyl). A sulfenyl may be substitutedor unsubstituted.

A “sulfinyl” group refers to an “—S(═O)—R” group in which R can be thesame as defined with respect to sulfenyl. A sulfinyl may be substitutedor unsubstituted.

A “sulfonyl” group refers to an “SO₂R” group in which R can be the sameas defined with respect to sulfenyl. A sulfonyl may be substituted orunsubstituted.

As used herein, “haloalkyl” refers to an alkyl group in which one ormore of the hydrogen atoms are replaced by a halogen (e.g.,mono-haloalkyl, di-haloalkyl and trio-haloalkyl). Such groups includebut are not limited to, chloromethyl, fluoromethyl, difluoromethyl,trifluoromethyl, 1-chloro-2-fluoromethyl and 2-fluoroisobutyl. Ahaloalkyl may be substituted or unsubstituted.

As used herein, “haloalkoxy” refers to an alkoxy group in which one ormore of the hydrogen atoms are replaced by a halogen (e.g.,mono-haloalkoxy, di-haloalkoxy and tri-haloalkoxy). Such groups includebut are not limited to, chloromethoxy, fluoromethoxy, difluoromethoxy,trifluoromethoxy, 1-chloro-2-fluoromethoxy and 2-fluoroisobutoxy. Ahaloalkoxy may be substituted or unsubstituted.

The term “amino” as used herein refers to a —NH₂ group.

A “mono-substituted amino” group refers to a “—NHR” group in which R canbe an alkyl, an alkenyl, an alkynyl, a cycloalkyl, a cycloalkenyl, aryl,heteroaryl, heterocyclyl, cycloalkyl(alkyl), aryl(alkyl),heteroaryl(alkyl) or heterocyclyl(alkyl), as defined herein. Amono-substituted amino may be substituted or unsubstituted. Examples ofmono-substituted amino groups include, but are not limited to,—NH(methyl), —NH(phenyl) and the like.

A “di-substituted amino” group refers to a “—NR_(A)R_(B)” group in whichR_(A) and R_(B) can be independently an alkyl, an alkenyl, an alkynyl, acycloalkyl, a cycloalkenyl, aryl, heteroaryl, heterocyclyl,cycloalkyl(alkyl), aryl(alkyl), heteroaryl(alkyl) orheterocyclyl(alkyl), as defined herein. A di-substituted amino may besubstituted or unsubstituted. Examples of di-substituted amino groupsinclude, but are not limited to, —N(methyl)₂, —N(phenyl)(methyl),—N(ethyl)(methyl) and the like.

Where the numbers of substituents is not specified (e.g. haloalkyl),there may be one or more substituents present. For example “haloalkyl”may include one or more of the same or different halogens. As anotherexample, “C₁-C₃ alkoxyphenyl” may include one or more of the same ordifferent alkoxy groups containing one, two or three atoms.

As used herein, a radical indicates species with a single, unpairedelectron such that the species containing the radical can be covalentlybonded to another species. Hence, in this context, a radical is notnecessarily a free radical. Rather, a radical indicates a specificportion of a larger molecule. The term “radical” can be usedinterchangeably with the term “group.”

As used herein, when a chemical group or unit includes an asterisk (*),that asterisk indicates a point of attachment of the group or unit toanother structure.

As used herein, “linking groups” are chemical groups that are indicatedas having multiple open valencies for connecting to two or more othergroups. For example, lower alkylene groups of the general formula—(CH₂)_(n)— where n is in the range of 1 to 10, are examples of linkinggroups that are described elsewhere herein as connecting molecularfragments via their terminal carbon atoms. Other examples of linkinggroups include —(CH₂)_(n)O—, —(CH₂)_(n)NH—, —(CH₂)_(n)N(C₁-C₆alkyl)-,and —(CH₂)_(n)S—, wherein each n is 0, 1, 2, 3, 4, 5, 6, 7, 8, 9, or 10.Those skilled in the art will recognize that n can be zero for somelinking groups such as —(CH₂)_(n)O—, in which case the linking group issimply —O—. Those skilled in the art will also recognize that referenceherein to an asymmetrical linking group will be understood as areference to all orientations of that group (unless stated otherwise).For example, reference herein to —(CH₂)_(n)O— will be understood as areference to both —(CH₂)_(n)O— and —O—(CH₂)_(n)—.

The term “pharmaceutically acceptable salt” refers to a salt of acompound that does not cause significant irritation to an organism towhich it is administered and does not abrogate the biological activityand properties of the compound. In some embodiments, the salt is an acidaddition salt of the compound. Pharmaceutical salts can be obtained byreacting a compound with inorganic acids such as hydrohalic acid (e.g.,hydrochloric acid or hydrobromic acid), a sulfuric acid, a nitric acidand a phosphoric acid (such as 2,3-dihydroxypropyl dihydrogenphosphate). Pharmaceutical salts can also be obtained by reacting acompound with an organic acid such as aliphatic or aromatic carboxylicor sulfonic acids, for example formic, acetic, succinic, lactic, malic,tartaric, citric, ascorbic, nicotinic, methanesulfonic, ethanesulfonic,p-toluensulfonic, trifluoroacetic, benzoic, salicylic,2-oxopentanedioic, or naphthalenesulfonic acid. Pharmaceutical salts canalso be obtained by reacting a compound with a base to form a salt suchas an ammonium salt, an alkali metal salt, such as a sodium, a potassiumor a lithium salt, an alkaline earth metal salt, such as a calcium or amagnesium salt, a salt of a carbonate, a salt of a bicarbonate, a saltof organic bases such as dicyclohexylamine, N-methyl-D-glucamine,tris(hydroxymethyl)methylamine, C₁-C₇ alkylamine, cyclohexylamine,triethanolamine, ethylenediamine, and salts with amino acids such asarginine and lysine. For compounds of Formula (I), those skilled in theart understand that when a salt is formed by protonation of anitrogen-based group (for example, NH₂), the nitrogen-based group can beassociated with a positive charge (for example, NH₂ can become NH₃ ⁺)and the positive charge can be balanced by a negatively chargedcounterion (such as Cl⁻).

It is understood that, in any compound described herein having one ormore chiral centers, if an absolute stereochemistry is not expresslyindicated, then each center may independently be of R-configuration orS-configuration or a mixture thereof. Thus, the compounds providedherein may be enantiomerically pure, enantiomerically enriched, racemicmixture, diastereomerically pure, diastereomerically enriched, or astereoisomeric mixture. In addition, it is understood that, in anycompound described herein having one or more double bond(s) generatinggeometrical isomers that can be defined as E or Z, each double bond mayindependently be E or Z a mixture thereof. Likewise, it is understoodthat, in any compound described, all tautomeric forms are also intendedto be included.

It is to be understood that where compounds disclosed herein haveunfilled valencies, then the valencies are to be filled with hydrogensor isotopes thereof, e.g., hydrogen-1 (protium) and hydrogen-2(deuterium).

It is understood that the compounds described herein can be labeledisotopically. Substitution with isotopes such as deuterium may affordcertain therapeutic advantages resulting from greater metabolicstability, such as, for example, increased in vivo half-life or reduceddosage requirements. Each chemical element as represented in a compoundstructure may include any isotope of said element. For example, in acompound structure a hydrogen atom may be explicitly disclosed orunderstood to be present in the compound. At any position of thecompound that a hydrogen atom may be present, the hydrogen atom can beany isotope of hydrogen, including but not limited to hydrogen-1(protium) and hydrogen-2 (deuterium). Thus, reference herein to acompound encompasses all potential isotopic forms unless the contextclearly dictates otherwise.

It is understood that the methods and combinations described hereininclude crystalline forms (also known as polymorphs, which include thedifferent crystal packing arrangements of the same elemental compositionof a compound), amorphous phases, salts, solvates, and hydrates. In someembodiments, the compounds described herein exist in solvated forms withpharmaceutically acceptable solvents such as water, ethanol, or thelike. In other embodiments, the compounds described herein exist inunsolvated form. Solvates contain either stoichiometric ornon-stoichiometric amounts of a solvent, and may be formed during theprocess of crystallization with pharmaceutically acceptable solventssuch as water, ethanol, or the like. Hydrates are formed when thesolvent is water, or alcoholates are formed when the solvent is alcohol.In addition, the compounds provided herein can exist in unsolvated aswell as solvated forms. In general, the solvated forms are consideredequivalent to the unsolvated forms for the purposes of the compounds andmethods provided herein.

Where a range of values is provided, it is understood that the upper andlower limit, and each intervening value between the upper and lowerlimit of the range is encompassed within the embodiments.

Terms and phrases used in this application, and variations thereof,especially in the appended claims, unless otherwise expressly stated,should be construed as open ended as opposed to limiting. As examples ofthe foregoing, the term ‘including’ should be read to mean ‘including,without limitation,’ ‘including but not limited to,’ or the like; theterm ‘comprising’ as used herein is synonymous with ‘including,’‘containing,’ or ‘characterized by,’ and is inclusive or open-ended anddoes not exclude additional, unrecited elements or method steps; theterm ‘having’ should be interpreted as ‘having at least;’ the term‘includes’ should be interpreted as ‘includes but is not limited to;’the term ‘example’ is used to provide exemplary instances of the item indiscussion, not an exhaustive or limiting list thereof; and use of termslike ‘preferably,’ ‘preferred,’ ‘desired,’ or ‘desirable,’ and words ofsimilar meaning should not be understood as implying that certainfeatures are critical, essential, or even important to the structure orfunction, but instead as merely intended to highlight alternative oradditional features that may or may not be utilized in a particularembodiment. In addition, the term “comprising” is to be interpretedsynonymously with the phrases “having at least” or “including at least”.When used in the context of a process, the term “comprising” means thatthe process includes at least the recited steps, but may includeadditional steps. When used in the context of a compound, composition ordevice, the term “comprising” means that the compound, composition ordevice includes at least the recited features or components, but mayalso include additional features or components. Likewise, a group ofitems linked with the conjunction ‘and’ should not be read as requiringthat each and every one of those items be present in the grouping, butrather should be read as ‘and/or’ unless the context indicatesotherwise. Similarly, a group of items linked with the conjunction ‘or’should not be read as requiring mutual exclusivity among that group, butrather should be read as ‘and/or’ unless the context indicatesotherwise.

With respect to the use of substantially any plural and/or singularterms herein, those having skill in the art can translate from theplural to the singular and/or from the singular to the plural as isappropriate to the context and/or application. The varioussingular/plural permutations may be expressly set forth herein for sakeof clarity. The indefinite article “a” or “an” does not exclude aplurality. The mere fact that certain measures are recited in mutuallydifferent dependent claims does not indicate that a combination of thesemeasures cannot be used to advantage. Any reference signs in the claimsshould not be construed as limiting the scope.

Compounds

Some embodiments disclosed herein relate to compounds of the Formula(I), or pharmaceutically acceptable salts thereof.

In various embodiments, compounds of Formula (I) are useful forameliorating, treating and/or diagnosing a disease or condition that isestrogen receptor dependent and/or estrogen receptor mediated. In anembodiment, the disease is cancer. In an embodiment, the cancer isbreast cancer. In an embodiment, compounds of Formula (I) are selectiveestrogen receptor modulators (SERMs). In an embodiment, compounds ofFormula (I) are selective estrogen receptor degraders (SERDs).Additional details regarding various uses and methods of treatment aredescribed elsewhere herein.

In various embodiments the variables X¹, Y¹ and Z¹ in Formula (I) areeach independently C or N, with the first proviso that at least one ofX¹, Y¹ and Z¹ is N; with the second proviso that each of X¹, Y¹ and Z¹is uncharged; with third proviso that two of the dotted lines indicatedouble bonds; and with the fourth proviso that the valencies of X¹, Y¹and Z¹ can be each independently satisfied by attachment to asubstituent selected from H and R¹². In an embodiment, the variable X²in Formula (I) is O, NH or S. For example, in an embodiment, X² is O. Invarious embodiments, R¹² is selected from the group consisting ofhydrogen, halogen, an optionally substituted C₁₋₃ alkyl, an optionallysubstituted C₁₋₃ haloalkyl and an optionally substituted C₁₋₃ alkoxy. Inan embodiment, R¹² is hydrogen. In another embodiment, R¹² is nothydrogen.

In an embodiment the variable A¹ in Formula (I) is selected from thegroup consisting of an optionally substituted cycloalkyl, an optionallysubstituted aryl, an optionally substituted heteroaryl and an optionallysubstituted heterocyclyl. In an embodiment A¹ is an optionallysubstituted aryl. For example, in an embodiment A¹ is an optionallysubstituted phenyl. Thus, in various embodiments A¹ is a substitutedphenyl or an unsubstituted phenyl. In another embodiment A¹ is anoptionally substituted cycloalkyl. For example, in an embodiment A¹ isan optionally substituted bicyclopentyl. Thus, in various embodiments A¹is a substituted bicyclopentyl or an unsubstituted bicyclopentyl.

In various embodiments the variable R¹ in Formula (I) is selected fromthe group consisting of an optionally substituted C₁₋₆ alkyl, anoptionally substituted cycloalkyl, an optionally substitutedcycloalkenyl, an optionally substituted aryl, an optionally substitutedheteroaryl, an optionally substituted heterocyclyl, an optionallysubstituted cycloalkyl(C₁₋₆ alkyl), an optionally substitutedcycloalkenyl(C₁₋₆ alkyl), an optionally substituted aryl(C₁₋₆ alkyl), anoptionally substituted heteroaryl(C₁₋₆ alkyl) and an optionallysubstituted heterocyclyl(C₁₋₆ alkyl). In an embodiment, R¹ is selectedfrom the group consisting of an optionally substituted C₁₋₆ alkyl, anoptionally substituted cycloalkyl, an optionally substitutedcycloalkyl(C₁₋₆ alkyl), an optionally substituted heterocyclyl and anoptionally substituted heterocyclyl(C₁₋₆ alkyl).

In an embodiment, R¹ in Formula (I) is a substituted cycloalkyl. In anembodiment, R¹ is substituted cycloalkyl that is substituted with one ormore substituents selected from the group consisting of halogen,hydroxy, haloalkyl, an optionally substituted alkyl, an optionallysubstituted cycloalkyl, a substituted alkoxy, a substitutedmono-substituted amine and a substituted di-substituted amine. In anembodiment, R¹ is an optionally substituted cycloalkyl selected from thegroup consisting of unsubstituted cyclobutyl, unsubstituteddifluorocyclobutyl, unsubstituted cyclopentyl and unsubstitutedbicyclopentyl. In an embodiment, R¹ is an optionally substitutedcycloalkyl(C₁₋₆ alkyl) selected from the group consisting ofunsubstituted cyclopropylmethyl, unsubstituted bicyclopentylmethyl,unsubstituted fluorocyclopropylmethyl, unsubstitutedfluorocyclobutylmethyl, unsubstituted methoxycyclopropylmethyl, andunsubstituted trifluoromethylcyclopropylmethyl. In an embodiment, R¹ isan optionally substituted heterocyclyl selected from the groupconsisting of unsubstituted tetrahydropyranyl, unsubstitutedtetrahydrofuranyl, and unsubstituted oxetanyl. In an embodiment, R¹ isan optionally substituted heterocyclyl(C₁₋₆ alkyl) is selected from thegroup consisting of unsubstituted oxetanylmethyl and unsubstitutedfluorooxetanylmethyl

In an embodiment, R¹ in Formula (I) is a substituted alkyl. In anembodiment, R¹ is a substituted alkyl that is substituted with one ormore substituents selected from the group consisting of halogen,hydroxy, haloalkyl, an optionally substituted cycloalkyl, a substitutedalkoxy, a substituted mono-substituted amine and a substituteddi-substituted amine. For example, in an embodiment, R¹ is a substitutedalkyl that is a haloalkyl. In another embodiment, R¹ is an optionallysubstituted C₁₋₆ alkyl selected from the group consisting of C₄ alkyl,fluoro(C₄ alkyl), and trifluoro(C₂ alkyl).

In various embodiments the variables R² and R³ in Formula (I) are eachindependently selected from the group consisting of hydrogen, halogen,an optionally substituted C₁₋₆ alkyl and an optionally substituted C₁₋₆haloalkyl. In other embodiments R² and R³ together with the carbon towhich R² and R³ are attached form an optionally substituted cycloalkyl,an optionally substituted cycloalkenyl or an optionally substitutedheterocyclyl. In an embodiment, R² is selected from the group consistingof hydrogen, methyl, fluoromethyl and difluoromethyl.

In various embodiments the variables R⁴ and R⁵ in Formula (I) are eachindependently selected from the group consisting of hydrogen, halogen,an optionally substituted C₁₋₆ alkyl and an optionally substituted C₁₋₆haloalkyl. In other embodiments R⁴ and R⁵ together with the carbon towhich R⁴ and R⁵ are attached form an optionally substituted cycloalkyl,an optionally substituted cycloalkenyl or an optionally substitutedheterocyclyl.

In various embodiments the variables R⁶, R⁷, R⁸ and R⁹ in Formula (I)are each independently selected from the group consisting of hydrogen,halogen, hydroxy, an optionally substituted alkyl, an optionallysubstituted alkoxy, an optionally substituted haloalkyl, an optionallysubstituted mono-substituted amine, and an optionally substituteddi-substituted amine. In an embodiment, R⁷ is selected from the groupconsisting of halogen, hydroxy, and unsubstituted alkoxy. For example,in an embodiment, R⁷ is selected from the group consisting of fluoro andmethoxy.

In various embodiments the variable R¹⁰ in Formula (I) is hydrogen,halogen, an optionally substituted alkyl, or an optionally substitutedcycloalkyl.

In various embodiments the variable R¹¹ in Formula (I) is hydrogen or anoptionally substituted C₁₋₆ alkyl. In an embodiment, R¹¹ is anunsubstituted C₁₋₆ alkyl. For example, in an embodiment, R¹¹ is methyl,ethyl or propyl (e.g., isopropyl or n-propyl).

In an embodiment, provided that when R¹¹ is hydrogen or methyl, X¹ isNH, Y¹ and Z¹ are each C, X² is O, A¹ is a phenyl, 2-fluorophenyl, or2,6-difluorophenyl, both R² and R³ are methyl or one of R² and R³ ishydrogen and the other of R² and R³ is methyl, and R⁴, R⁵, R⁶, R⁷, R⁸,R⁹ and R¹⁰ are each hydrogen, then R¹ cannot be 2-hydroxyethyl,2-methylpropyl, 2-fluoro-2-methylpropyl, 3-fluoro-2-methylpropyl,3-hydroxy-2-methylpropyl or 2-fluoro-3-hydroxy-2-methylpropyl.

In another embodiment, provided that when R¹⁰ is hydrogen, R¹¹ ishydrogen or methyl, X¹ is NH, Y¹ and Z¹ are each C, X² is O, A¹ is anoptionally substituted phenyl, one of R² and R³ is hydrogen or anoptionally substituted C₁₋₆ alkyl and the other of R² and R³ is anoptionally substituted C₁₋₆ alkyl, then R¹ cannot be a substituted C₁₋₆alkyl substituted with one or more substituents selected from the groupconsisting of halogen and hydroxy.

Various embodiments provide compounds of the Formula (I), orpharmaceutically acceptable salts thereof, where the compounds of theFormula (I) can be represented by Formulae (Ia), (Ib), (Ic), or (Id),having the structures below.

In various embodiments, the variables R¹, R⁶, R⁷, R⁸ and R¹⁰ for thecompounds of Formulae (Ia), (Ib), (Ic) and (Id) are the same asdescribed elsewhere herein.

In an embodiment, the variable R¹ in Formulae (Ia), (Ib), (Ic) and (Id)is an optionally substituted C₁₋₆ alkyl selected from the groupconsisting of C₄ alkyl, fluoro(C₄ alkyl), and trifluoro(C₂ alkyl). Inanother embodiment, the variable R¹ in Formulae (Ia), (Ib), (Ic) and(Id) is an optionally substituted cycloalkyl selected from the groupconsisting of unsubstituted cyclobutyl, unsubstituteddifluorocyclobutyl, unsubstituted cyclopentyl and unsubstitutedbicyclopentyl. In another embodiment, the variable R¹ in Formulae (Ia),(Ib), (Ic) and (Id) is an optionally substituted cycloalkyl(C₁₋₆ alkyl)selected from the group consisting of unsubstituted cyclopropylmethyl,unsubstituted bicyclopentylmethyl, unsubstitutedfluorocyclopropylmethyl, unsubstituted fluorocyclobutylmethyl,unsubstituted methoxycyclopropylmethyl, and unsubstitutedtrifluoromethylcyclopropylmethyl. In another embodiment, the variable R¹in Formulae (Ia), (Ib), (Ic) and (Id) is an optionally substitutedheterocyclyl selected from the group consisting of unsubstitutedtetrahydropyranyl, unsubstituted tetrahydrofuranyl, and unsubstitutedoxetanyl. In another embodiment, the variable R¹ in Formulae (Ia), (Ib),(Ic) and (Id). In another embodiment, the variable R¹ in Formulae (Ia),(Ib), (Ic) and (Id) is an optionally substituted heterocyclyl(C₁₋₆alkyl) selected from the group consisting of unsubstitutedoxetanylmethyl and unsubstituted fluorooxetanylmethyl. In variousembodiments, when the variables R⁶, R⁷ and R⁸ are hydrogen, the variableR¹ in Formulae (Ia), (Ib), (Ic) and (Id) cannot be 2-hydroxyethyl,2-methylpropyl, 2-fluoro-2-methylpropyl, 3-fluoro-2-methylpropyl,3-hydroxy-2-methylpropyl or 2-fluoro-3-hydroxy-2-methylpropyl.

In an embodiment, the variables R⁶, R⁷ and R⁸ in Formulae (Ia), (Ib),(Ic) and (Id) are each independently selected from the group consistingof halogen e.g., fluoro, chloro or bromo), hydroxy, and unsubstitutedalkoxy (e.g., methoxy, ethoxy or propoxy). In another embodiment, thevariables R⁶ and R⁸ in Formulae (Ia), (Ib), (Ic) and (Id) are bothhydrogen. In another embodiment, the variables R⁶ and R⁷ in Formulae(Ia), (Ib), (Ic) and (Id) are both hydrogen. In another embodiment, thevariables R⁷ and R⁸ in Formulae (Ia), (Ib), (Ic) and (Id) are bothhydrogen.

In an embodiment, the variable R¹⁰ in Formulae (Ia), (Ib), (Ic) and (Id)is hydrogen or a C₁₋₆ alkyl. In an embodiment, the variable R¹⁰ inFormulae (Ia), (Ib), (Ic) and (Id) is not hydrogen.

Various embodiments provide compounds of the Formula (I), orpharmaceutically acceptable salts thereof, where the compounds of theFormula (I) can be represented by Formulae (Ie), (If), (Ig) and (Ih),having the structures below.

In various embodiments, the variables R¹, R⁷, and R¹⁰ for the compoundsof Formulae (Ie), (If), (Ig) and (Ih) are the same as describedelsewhere herein.

In an embodiment, the variable R¹ in Formulae (Ie), (If), (Ig) and (Ih)is an optionally substituted C₁₋₆ alkyl selected from the groupconsisting of C₄ alkyl, fluoro(C₄ alkyl), and trifluoro(C₂ alkyl). Inanother embodiment, the variable R¹ in Formulae (Ie), (If), (Ig) and(Ih) is an optionally substituted cycloalkyl selected from the groupconsisting of unsubstituted cyclobutyl, unsubstituteddifluorocyclobutyl, unsubstituted cyclopentyl and unsubstitutedbicyclopentyl. In another embodiment, the variable R¹ in Formulae (Ie),(If), (Ig) and (Ih) is an optionally substituted cycloalkyl(C₁₋₆ alkyl)selected from the group consisting of unsubstituted cyclopropylmethyl,unsubstituted bicyclopentylmethyl, unsubstitutedfluorocyclopropylmethyl, unsubstituted fluorocyclobutylmethyl,unsubstituted methoxycyclopropylmethyl, and unsubstitutedtrifluoromethylcyclopropylmethyl. In another embodiment, the variable R¹in Formulae (Ie), (If), (Ig) and (Ih) is an optionally substitutedheterocyclyl selected from the group consisting of unsubstitutedtetrahydropyranyl, unsubstituted tetrahydrofuranyl, and unsubstitutedoxetanyl. In another embodiment, the variable R¹ in Formulae (Ie), (If),(Ig) and (Ih). In another embodiment, the variable R¹ in Formulae (Ie),(If), (Ig) and (Ih) is an optionally substituted heterocyclyl(C₁₋₆alkyl) selected from the group consisting of unsubstitutedoxetanylmethyl and unsubstituted fluorooxetanylmethyl. In variousembodiments, when the variable R⁷ is hydrogen, the variable R¹ inFormulae (Ie), (If), (Ig) and (Ih) cannot be 2-hydroxyethyl,2-methylpropyl, 2-fluoro-2-methylpropyl, 3-fluoro-2-methylpropyl,3-hydroxy-2-methylpropyl or 2-fluoro-3-hydroxy-2-methylpropyl.

In an embodiment, the variable R⁷ in Formulae (Ie), (If), (Ig) and (Ih)is selected from the group consisting of halogen (e.g., fluoro, chloroor bromo), hydroxy, and unsubstituted alkoxy (e.g., methoxy, ethoxy orpropoxy). In an embodiment, the variable R¹⁰ in Formulae (Ie), (If),(Ig) and (Ih) is hydrogen or a C₁₋₆ alkyl. In an embodiment, thevariable R¹⁰ in Formulae (Ie), (If), (Ig) and (Ih) is not hydrogen.

Methods of Making

Compounds of the Formula (I), or pharmaceutically acceptable saltsthereof, can be made in various ways by those skilled using knowntechniques as guided by the detailed teachings provided herein. Forexample, in an embodiment, compounds of the Formula (I) are prepared inaccordance with General Scheme 1 as shown in FIG. 1. The variables inGeneral Scheme 1 are as described elsewhere herein with respect to theFormula (I). In general, the ring formation and coupling reactionbetween compounds of the general formulae (A) and (B) to form compoundsof the Formula (I) as illustrated in General Scheme 1 can be carried outin a manner similar to that of the reaction between(R)—N-(1-(1H-indol-3-yl)propan-2-yl)-2-fluoro-2-methylpropan-1-amine andethyl (E)-3-(3-formylbicyclo[1.1.1]pentan-1-yl)acrylate as described inExample 1A below. Any preliminary reaction steps required to formstarting compounds of the general formulae (A) and (B) can be readilycarried out by those skilled in the art in view of the detailed teachingprovided herein, e.g., by appropriate adjustment of the reagents andconditions described in Example 1A for the preparation of(R)—N-(1-(1H-indol-3-yl)propan-2-yl)-2-fluoro-2-methylpropan-1-amine andethyl (E)-3-(3-formylbicyclo[1.1.1]pentan-1-yl)acrylate, respectively.Similarly, any intermediate reaction products formed as a result of thereaction between compounds of the general formulae (A) and (B) can bereadily converted to compounds of the Formula (I) by those skilled inthe art in view of the detailed teaching provided herein, e.g., byappropriate adjustment of the reagents and conditions described inExample 1A for the preparation of Compound 1A from intermediate ethyl(E)-3-(3-((1R,3R)-2-(2-fluoro-2-methylpropyl)-3-methyl-2,3,4,9-tetrahydro-1H-pyrido[3,4-b]indol-1-yl)bicyclo[1.1.1]pentan-1-yl)acrylate.

Uses and Methods of Treatment

As described herein, one or more compounds of Formula (I), orpharmaceutically acceptable salts thereof, or a pharmaceuticalcomposition as described herein, can be used to inhibit the growth of acell. In an embodiment, the cell is identified as having an estrogenreceptor that mediates a growth characteristic of the cell. Growth of acell can be inhibited by contacting the cell with an effective amount ofat least one of the compounds described herein, or pharmaceuticallyacceptable salts thereof, or a pharmaceutical composition as describedelsewhere herein. Such contacting of the one or more compounds, orpharmaceutically acceptable salts thereof, can take place in variousways and locations, including without limitation away from a livingsubject (e.g., in a laboratory, diagnostic and/or analytical setting) orin proximity to a living subject (e.g., within or on an exterior portionof an animal, e.g., a human). For example, an embodiment provides amethod of treating a subject, comprising identifying a subject that isin need of treatment for a disease or condition that is estrogenreceptor dependent and/or estrogen receptor mediated and administeringto said subject an effective amount of one or more compounds of Formula(I), or a pharmaceutically acceptable salt thereof, or a pharmaceuticalcomposition, as described elsewhere herein. Another embodiment providesa use of one or more compounds of Formula (I), or a pharmaceuticallyacceptable salt thereof, or a pharmaceutical composition (as describedelsewhere herein), in the manufacture of a medicament for the treatmentof a disease or condition that is estrogen receptor alpha dependentand/or estrogen receptor alpha mediated.

Non-limiting examples of diseases or conditions that are estrogenreceptor alpha dependent and/or estrogen alpha receptor mediated andthus suitable for treatment using the compounds, compositions andmethods described herein include breast cancers and gynecologicalcancers. For example, such diseases or conditions may include one ormore of the following: breast cancer, endometrial cancer, ovarian cancerand cervical cancer. An embodiment provides a use of one or morecompounds of Formula (I), or a pharmaceutically acceptable salt thereof,or a pharmaceutical composition (as described elsewhere herein), in themanufacture of a medicament for the treatment of breast cancers andgynecological cancers, including for example one or more of thefollowing: breast cancer, endometrial cancer, ovarian cancer andcervical cancer.

As described herein, compounds of Formula (I), or a pharmaceuticallyacceptable salt thereof, or a pharmaceutical composition as describedelsewhere herein, can be administered to such subjects by a variety ofmethods. In any of the uses or methods described herein, administrationcan be by various routes known to those skilled in the art, includingwithout limitation oral, intravenous, intramuscular, topical,subcutaneous, systemic, and/or intraperitoneal administration to asubject in need thereof.

As used herein, the terms “treat,” “treating,” “treatment,”“therapeutic,” and “therapy” do not necessarily mean total cure orabolition of the estrogen receptor dependent and/or estrogen receptormediated disease or condition. Any alleviation of any undesired signs orsymptoms of the disease or condition, to any extent can be consideredtreatment and/or therapy. Furthermore, treatment may include acts thatmay worsen the subject's overall feeling of well-being or appearance.

The terms “therapeutically effective amount” and “effective amount” areused to indicate an amount of an active compound, or pharmaceuticalagent, that elicits the biological or medicinal response indicated. Forexample, a therapeutically effective amount of compound, salt orcomposition can be the amount needed to prevent, alleviate or amelioratesymptoms of the estrogen receptor dependent and/or estrogen receptormediated disease or condition, or prolong the survival of the subjectbeing treated This response may occur in a tissue, system, animal orhuman and includes alleviation of the signs or symptoms of the estrogenreceptor dependent and/or estrogen receptor mediated disease orcondition being treated. Determination of an effective amount is wellwithin the capability of those skilled in the art, in view of thedisclosure provided herein. The therapeutically effective amount of thecompounds disclosed herein required as a dose will depend on the routeof administration, the type of animal, including human, being treated,and the physical characteristics of the specific animal underconsideration. The dose can be tailored to achieve a desired effect, butwill depend on such factors as weight, diet, concurrent medication andother factors which those skilled in the medical arts will recognize.

The amount of the compound of Formula (I), or a pharmaceuticallyacceptable salt thereof, required for use in treatment will vary notonly with the particular compound or salt selected but also with theroute of administration, the nature and/or symptoms of the estrogenreceptor dependent and/or estrogen receptor mediated disease orcondition being treated and the age and condition of the patient andwill be ultimately at the discretion of the attendant physician orclinician. In cases of administration of a pharmaceutically acceptablesalt, dosages may be calculated as the free base. As will be understoodby those of skill in the art, in certain situations it may be necessaryto administer the compounds disclosed herein in amounts that exceed, oreven far exceed, the dosage ranges described herein in order toeffectively and aggressively treat particularly aggressive estrogenreceptor dependent and/or estrogen receptor mediated diseases orconditions.

In general, however, a suitable dose will often be in the range of fromabout 0.05 mg/kg to about 10 mg/kg. For example, a suitable dose may bein the range from about 0.10 mg/kg to about 7.5 mg/kg of body weight perday, such as about 0.15 mg/kg to about 5.0 mg/kg of body weight of therecipient per day, about 0.2 mg/kg to 4.0 mg/kg of body weight of therecipient per day. The compound may be administered in unit dosage form;for example, containing 1 to 500 mg, 10 to 100 mg or 5 to 50 mg ofactive ingredient per unit dosage form.

The desired dose may conveniently be presented in a single dose or asdivided doses administered at appropriate intervals, for example, astwo, three, four or more sub-doses per day. The sub-dose itself may befurther divided, e.g., into a number of discrete loosely spacedadministrations.

As will be readily apparent to one skilled in the art, the useful invivo dosage to be administered and the particular mode of administrationwill vary depending upon the age, weight, the severity of theaffliction, and mammalian species treated, the particular compoundsemployed, and the specific use for which these compounds are employed.The determination of effective dosage levels, that is the dosage levelsnecessary to achieve the desired result, can be accomplished by oneskilled in the art using routine methods, for example, human clinicaltrials, in vivo studies and in vitro studies. For example, usefuldosages of a compound of Formula (I), or pharmaceutically acceptablesalts thereof, can be determined by comparing their in vitro activity,and in vivo activity in animal models. Such comparison can be done bycomparison against an established drug, such as fulvestrant.

Dosage amount and interval may be adjusted individually to provideplasma levels of the active moiety which are sufficient to maintain themodulating effects, or minimal effective concentration (MEC). The MECwill vary for each compound but can be estimated from in vivo and/or invitro data. Dosages necessary to achieve the MEC will depend onindividual characteristics and route of administration. However, HPLCassays or bioassays can be used to determine plasma concentrations.Dosage intervals can also be determined using MEC value. Compositionsshould be administered using a regimen which maintains plasma levelsabove the MEC for 10-90% of the time, preferably between 30-90% and mostpreferably between 50-90%. In cases of local administration or selectiveuptake, the effective local concentration of the drug may not be relatedto plasma concentration.

It should be noted that the attending physician would know how to andwhen to terminate, interrupt, or adjust administration due to toxicityor organ dysfunctions. Conversely, the attending physician would alsoknow to adjust treatment to higher levels if the clinical response werenot adequate (precluding toxicity). The magnitude of an administrateddose in the management of the disorder of interest will vary with theseverity of the estrogen receptor dependent and/or estrogen receptormediated disease or condition to be treated and to the route ofadministration. The severity of the estrogen receptor dependent and/orestrogen receptor mediated disease or condition may, for example, beevaluated, in part, by standard prognostic evaluation methods. Further,the dose and perhaps dose frequency, will also vary according to theage, body weight, and response of the individual patient. A programcomparable to that discussed above may be used in veterinary medicine.

Compounds, salts and compositions disclosed herein can be evaluated forefficacy and toxicity using known methods. For example, the toxicologyof a particular compound, or of a subset of the compounds, sharingcertain chemical moieties, may be established by determining in vitrotoxicity towards a cell line, such as a mammalian, and preferably human,cell line. The results of such studies are often predictive of toxicityin animals, such as mammals, or more specifically, humans.Alternatively, the toxicity of particular compounds in an animal model,such as mice, rats, rabbits, dogs or monkeys, may be determined usingknown methods. The efficacy of a particular compound may be establishedusing several recognized methods, such as in vitro methods, animalmodels, or human clinical trials. When selecting a model to determineefficacy, the skilled artisan can be guided by the state of the art tochoose an appropriate model, dose, route of administration and/orregime.

Pharmaceutical Compositions

Some embodiments described herein relate to a pharmaceuticalcomposition, that can include an effective amount of one or morecompounds described herein (e.g., a compound of Formula (I), or apharmaceutically acceptable salt thereof) and a pharmaceuticallyacceptable carrier, diluent, excipient or combination thereof.

The term “pharmaceutical composition” refers to a mixture of one or morecompounds and/or salts disclosed herein with other chemical components,such as diluents or carriers. The pharmaceutical composition facilitatesadministration of the compound to an organism. Pharmaceuticalcompositions can also be obtained by reacting compounds with inorganicor organic acids such as hydrochloric acid, hydrobromic acid, sulfuricacid, nitric acid, phosphoric acid, methanesulfonic acid, ethanesulfonicacid, p-toluenesulfonic acid, and salicylic acid. Pharmaceuticalcompositions will generally be tailored to the specific intended routeof administration.

The term “physiologically acceptable” defines a carrier, diluent orexcipient that does not abrogate the biological activity and propertiesof the compound nor cause appreciable damage or injury to an animal towhich delivery of the composition is intended.

As used herein, a “carrier” refers to a compound that facilitates theincorporation of a compound into cells or tissues. For example, withoutlimitation, dimethyl sulfoxide (DMSO) is a commonly utilized carrierthat facilitates the uptake of many organic compounds into cells ortissues of a subject.

As used herein, a “diluent” refers to an ingredient in a pharmaceuticalcomposition that lacks appreciable pharmacological activity but may bepharmaceutically necessary or desirable. For example, a diluent may beused to increase the bulk of a potent drug whose mass is too small formanufacture and/or administration. It may also be a liquid for thedissolution of a drug to be administered by injection, ingestion orinhalation. A common form of diluent in the art is a buffered aqueoussolution such as, without limitation, phosphate buffered saline thatmimics the pH and isotonicity of human blood.

As used herein, an “excipient” refers to an essentially inert substancethat is added to a pharmaceutical composition to provide, withoutlimitation, bulk, consistency, stability, binding ability, lubrication,disintegrating ability etc., to the composition. For example,stabilizers such as anti-oxidants and metal-chelating agents areexcipients. In an embodiment, the pharmaceutical composition comprisesan anti-oxidant and/or a metal-chelating agent. A “diluent” is a type ofexcipient.

The pharmaceutical compositions described herein can be administered toa human patient per se, or in pharmaceutical compositions where they aremixed with other active ingredients, as in combination therapy, orcarriers, diluents, excipients or combinations thereof. Properformulation is dependent upon the route of administration chosen.Techniques for formulation and administration of the compounds describedherein are known to those skilled in the art.

The pharmaceutical compositions disclosed herein may be manufactured ina manner that is itself known, e.g., by means of conventional mixing,dissolving, granulating, dragee-making, levigating, emulsifying,encapsulating, entrapping or tableting processes. Additionally, theactive ingredients are contained in an amount effective to achieve itsintended purpose. Many of the compounds used in the pharmaceuticalcombinations disclosed herein may be provided as salts withpharmaceutically compatible counterions.

Multiple techniques of administering a compound, salt and/or compositionexist in the art including, but not limited to, oral, rectal, pulmonary,topical, aerosol, injection, infusion and parenteral delivery, includingintramuscular, subcutaneous, intravenous, intramedullary injections,intrathecal, direct intraventricular, intraperitoneal, intranasal andintraocular injections.

One may also administer the compound, salt and/or composition in a localrather than systemic manner, for example, via injection or implantationof the compound directly into the affected area, often in a depot orsustained release formulation. Furthermore, one may administer thecompound in a targeted drug delivery system, for example, in a liposomecoated with a tissue-specific antibody. The liposomes will be targetedto and taken up selectively by the organ. For example, intranasal orpulmonary delivery to target a respiratory disease or condition may bedesirable.

The compositions may, if desired, be presented in a pack or dispenserdevice which may contain one or more unit dosage forms containing theactive ingredient. The pack may for example comprise metal or plasticfoil, such as a blister pack. The pack or dispenser device may beaccompanied by instructions for administration. The pack or dispensermay also be accompanied with a notice associated with the container inform prescribed by a governmental agency regulating the manufacture,use, or sale of pharmaceuticals, which notice is reflective of approvalby the agency of the form of the drug for human or veterinaryadministration. Such notice, for example, may be the labeling approvedby the U.S. Food and Drug Administration for prescription drugs, or theapproved product insert. Compositions that can include a compound and/orsalt described herein formulated in a compatible pharmaceutical carriermay also be prepared, placed in an appropriate container, and labeledfor treatment of an indicated condition.

EXAMPLES

Additional embodiments are disclosed in further detail in the followingexamples, which are not in any way intended to limit the scope of theclaims.

Compounds

The compounds of Formula (I) illustrated in Table 1 can be prepared invarious ways, using techniques known to those skilled in the art asguided by the detailed teachings provided herein. For example, thecompounds of Formula (I) illustrated in Table 1 can be prepared inaccordance with General Scheme 1 as described in the Examples below.Likewise, the compounds of Formula (I) illustrated in Table 2 can bereadily prepared in accordance with General Scheme 1 in view of thedetailed teachings set forth in the Examples below. Those skilled in theart will understand that a number of structures shown in Table 1 are notstereospecific and/or are depicted as having unfilled valencies, andthus are generic to isotopic and/or stereochemical variants, includingracemates, diastereomers, enantiomers and/or deuterated versions, whichcan be prepared in accordance with the guidance provided herein.

TABLE 1 No. Compound Structure 1

1A

1B

2

2A

3

3A

4

4A

4B

5

5A

5B

5C

6

6A

7

7A

8

8A

8B

8C

9

9A

9B

10

10A

11

11A

11B

11C

11D

12

12A

13

13A

13B

14

14A

15

15A

16

16A

17

17A

18

18A

19

19A

20

21

21A

22

23

23A

23B

24

25

25A

25B

26

26A

TABLE 2 No. Compound Structure 27

28

29

30

31

32

33

34

35

36

37

38

39

40

41

42

43

44

45

46

47

48

49

50

51

Example 1A(E)-3-(3-((1R,3R)-2-(2-Fluoro-2-methylpropyl)-3-methyl-2,3,4,9-tetrahydro-1H-pyrido[3,4-b]indol-1-yl)bicyclo[1.1.1]pentan-1-yl)acrylicacid (1A)

Synthesis of Intermediate 2-fluoro-2-methylpropyltrifluoromethanesulfonate Step 1

To a stirred solution of ethyl 2-fluoro-2-methylpropanoate (500 mg, 3.72mmol) in diethyl ether (10 mL) was added lithium aluminium hydride (352mg, 9.28 mmol) at 0° C. The reaction was stirred at room temperature for16 h and quenched with 0.3 mL of 15% aqueous NaOH solution at 0° C.,followed by 1 mL of water. The mixture was stirred at room temperaturefor 20 min and filtered through a Celite pad which was washed withdiethyl ether (10 mL). The filtrate was concentrated (bath temperature30° C.) to afford 2-fluoro-2-methylpropan-1-ol (210 mg, 61% yield) ascolorless liquid which was used without further purification.

Step 2

To a stirred solution of 2-fluoro-2-methylpropan-1-ol (12 g, 130 mmol)in dichloromethane (120 mL) was added 2,6-lutidine (16.6 g, 155 mmol)and the mixture was cooled to −78° C. Trifluoromethane sulfonicanhydride (25.7 mL, 155 mmol) was added and the reaction was stirred atroom temperature for 2 h. The reaction mixture was quenched with icewater (200 mL) and extracted with dichloromethane (2×500 mL). Thecombined organic layers were washed with water (4×300 mL) and dried oversodium sulfate and concentrated to get a crude red oil. The crudecompound was purified by fractional distillation (bath temperature 80°C. to 100° C. at 5 mbar) to afford 2-fluoro-2-methylpropyltrifluoromethanesulfonate (4.8 g, 16% yield) as a colorless liquid. ¹HNMR (400 MHz, CDCl₃) δ=4.41 (d, J=18 Hz, 2H), 1.46 (d, J=21.2 Hz, 6H).

Synthesis of Intermediate (R)-1-(1H-indol-3-yl)propan-2-amine Step 1

To a stirred suspension of LAH (37.3 g, 984 mmol), in dry THF (2.5 L)was added L-tryptophan (50 g, 245 mmol) at 0° C. and heated at 65° C.for 18 h. To the reaction mixture was added saturated aqueous Na₂SO₄solution (300 mL) at 0° C. The resulting suspension was filtered througha celite pad. The pad was washed with EtOAc (2 L) and the combinedorganics dried over Na₂SO₄, filtered and evaporated under reducedpressure to afford (S)-2-amino-3-(1H-indol-3-yl)propan-1-ol (45.3 g) asyellow thick liquid. This compound was used directly in the next stepwithout further purification. (45.3 g, 97% yield). MS (ESI) m/z 191.22[M+H]⁺.

Step 2

Benzyl chloroformate (41.2 g, 241 mmol) was added dropwise to asuspension of Na₂CO₃ (43.1 g, 407 mmol) and(S)-2-amino-3-(1H-indol-3-yl)propan-1-ol (45 g, 237 mmol) in a 1:1solution of water and acetone (2 L) at 0° C. After addition, the coolingbath was removed and the resulting reaction mixture was stirred at rtfor 4 h. The reaction mixture was cooled to 0° C., slowly acidified topH˜2 with concentrated HCl, diluted with water and then extracted withethyl acetate (3×). The combined organic layer was dried over Na₂SO₄,filtered and evaporated under reduced pressure to obtain the crudeproduct which was purified by flash column chromatography (SiO₂, 40 to70% EtOAc/Hexane) to afford benzyl(S)-(1-hydroxy-3-(1H-indol-3-yl)propan-2-yl)carbamate as a yellow thickliquid. (38 g, 49% yield). MS (ESI) m/z 324.93 [M+H]⁺.

Step 3

p-Toluenesulfonyl chloride (21.2 g, 111 mmol) was added to a solution ofbenzyl (S)-(1-hydroxy-3-(1H-indol-3-yl)propan-2-yl)carbamate (34 g, 105mmol) and TEA (20.7 g, 204 mmol) in dry DCM (350 mL) at 0° C. Afteraddition, the cooling bath was removed and the resulting reactionmixture was stirred at room temperature for 16 h. Solvent was evaporatedunder reduced pressure. The crude residue was purified by flash columnchromatography (SiO₂, 30 to 50% EtOAc/Hexane) to afford(S)-2-(((benzyloxy)carbonyl)amino)-3-(1H-indol-3-yl)propyl4-methylbenzenesulfonate as a pale brown solid. (42 g, 83% yield). MS(ESI) m/z 479.16 [M+H]⁺.

Step 4

To a stirred solution of compound(S)-2-(((benzyloxy)carbonyl)amino)-3-(1H-indol-3-yl)propyl4-methylbenzenesulfonate (42 g, 87.8 mmol) in absolute ethanol (2.9 L)was added Pd(OH)₂ (5.18 g, 36.9 mmol) and the resulting reaction mixturewas stirred an atmosphere of hydrogen gas (150 psi) for 5 h. The mixturewas filtered through a Celite pad and the pad was washed with EtOAc (1.5L) and evaporated under reduced pressure. The crude product was furtherpurified by flash column chromatography (SiO₂, 15% methanol/5% NH₄OH inDCM) to afford (R)-1-(1H-indol-3-yl)propan-2-amine as off white solid.(4.3 g, 28% yield). ¹H NMR (300 MHz, DMSO-d₆) δ 10.79 (s, 1H), 7.51 (d,J=7.8 Hz, 1H), 7.32 (d, J=7.8 Hz, 1H), 7.11 (d, J=2.1 Hz, 1H), 7.04(ddd, J=0.9 Hz, 6.9 Hz, 8.1 Hz, 1H), 6.95 (ddd, J=1.2 Hz, 6.9 Hz, 7.8Hz, 1H), 3.15-3.02 (m, 1H), 2.63 (d, J=6.6 Hz, 2H), 1.82-1.59 (br s 2H),0.98 (d, J=6.3 Hz, 3H); MS (ESI) m/z 174.24 [M+H]+; [α]_(D)=−34.2°(c=0.5, MeOH).

Synthesis of Intermediate ethyl(E)-3-(3-formylbicyclo[1.1.1]pentan-1-yl)acrylate Step 1

To a suspension of 3-(methoxycarbonyl)bicyclo[1.1.1]pentane-1-carboxylicacid (12 g, 70.5 mmol) in dry THF (200 mL) was added BH₃-THF (84 mL,84.0 mmol, 1.0M in THF) dropwise under argon at 0° C. The mixture wasstirred at the same temperature for 1 h. A standard aqueous workup andcolumn purification (SiO₂, EtOAc/Hexanes) provided 10.1 g (Yield: 91%)of methyl 3-(hydroxymethyl)bicyclo[1.1.1]pentane-1-carboxylate of theformula

Step 2

To a suspension of methyl3-(hydroxymethyl)bicyclo[1.1.1]pentane-1-carboxylate (9 g, 57.7 mmol) indry DCM (200 mL) was added imidazole (7.8 g, 114 mmol) and TBDMS-Cl(10.3 g, 68.3 mmol) at 0° C. The reaction was allowed to stir at rt for2 h. Standard aqueous work-up and column purification (SiO₂,EtOAc/Hexanes) provided 14.5 g (Yield: 93%) of methyl3-(((tert-butyldimethylsilyl)oxy)methyl)bicyclo[1.1.1]pentane-1-carboxylateof the formula

Step 3

To a suspension of methyl3-(((tert-butyldimethylsilyl)oxy)methyl)bicyclo[1.1.1]pentane-1-carboxylate(7 g, 25.9 mmol) in dry toluene (70 mL) was added DIBAL-H (31.1 mL, 31.1mmol, 1M in toluene) at −78° C. followed by stirring for 1 h at the sametemperature. Standard aqueous work-up followed by column purification(SiO₂, EtOAc/Hexanes) provided 4.7 g (Yield: 75%) of3-(((tert-butyldimethylsilyl)oxy)methyl)bicyclo[1.1.1]pentane-1-carbaldehydeof the formula

Step 4

To a stirred suspension of3-(((tert-butyldimethylsilyl)oxy)methyl)bicyclo[1.1.1]pentane-1-carbaldehyde(5 g, 20.8 mmol) in 45 mL of dry THF, NaH (1.01 g, 31.2 mmol) was addedat 0° C. The reaction was stirred at rt for 1 h. Ethyl2-(diethoxyphosphoryl)acetate (3.74 g, 14.5 mmol) was added at 0° C. Themixture was allowed to stir at rt for 3 h. Standard aqueous work-up andcolumn purification (SiO₂, EtOAc/Hexanes) provided 3 g (Yield: 42%) ofethyl(E)-3-(3-(((tert-butyldimethylsilyl)oxy)methyl)bicyclo[1.1.1]pentan-1-yl)acrylateof the formula

Step 5

To a stirred solution of ethyl(E)-3-(3-(((tert-butyldimethylsilyl)oxy)methyl)bicyclo[1.1.1]pentan-1-yl)acrylate(0.6 g, 1.93 mmol) in dry THF (10 mL) at 0° C. was added TBAF (1.0 g,3.86 mmol). The mixture was stirred at rt for 18 h. Standard aqueouswork-up and column purification (SiO₂, EtOAc/Hexanes) provided 195 mg(Yield: 54%) of ethyl(E)-3-(3-(hydroxymethyl)bicyclo[1.1.1]pentan-1-yl)acrylate of theformula

as a colorless liquid.

Step 6

To a stirred solution of ethyl(E)-3-(3-(hydroxymethyl)bicyclo[1.1.1]pentan-1-yl)acrylate (195 mg,0.994 mmol) in DCM (8 mL) was added Dess-Martin periodinane (84 mg, 1.99mmol) at 0° C. The resulting mixture was stirred rt for 2 h. Standardaqueous work-up and column purification (SiO₂, EtOAc/Hexanes) provided135 mg (Yield: 77%) of ethyl(E)-3-(3-formylbicyclo[1.1.1]pentan-1-yl)acrylate of the formula

as a colorless liquid. ¹H NMR (400 MHz, CDCl₃) δ 9.60 (s, 1H), 6.94 (d,J=15.6 Hz, 1H), 5.82 (d, J=15.6 Hz, 1H), 4.20 (q, J=4.0 Hz, 2H), 2.16(s, 6H), 1.30 (t, J=4.0 Hz, 3H).

Synthesis of Compound 1A Step 1

To a stirred solution of (R)-1-(1H-indol-3-yl)propan-2-amine (2 g, 11.4mmol) in dioxane (10 mL) was added 2-fluoro-2-methylpropyltrifluoromethanesulfonate (2.55 g, 11.4 mmol) andN,N-diisopropylethylamine (3.08 mL, 17.4 mmol). The mixture was stirredat 90° C. for 3 h and then diluted with ethyl acetate (10 mL) and washedwith saturated aqueous NaHCO₃ solution (10 mL). The combined organicswere dried over sodium sulfate, filtered and concentrated. The resultantresidue was purified by column chromatography (SiO₂, 40-50%EtOAc/Hexane) to afford 2.19 g (76% yield) of(R)—N-(1-(1H-indol-3-yl)propan-2-yl)-2-fluoro-2-methylpropan-1-amine. MS(ESI) m/z 249.14 [M+H]⁺.

Step 2

To a stirred solution of(R)—N-(1-(1H-indol-3-yl)propan-2-yl)-2-fluoro-2-methylpropan-1-amine(250 mg, 1.06 mmol) and ethyl(E)-3-(3-formylbicyclo[1.1.1]pentan-1-yl)acrylate in 5 ml of toluene wasadded acetic acid (64 mg, 1.01 mmol) and the mixture was stirred at 90°C. for 5 h. The reaction mixture was diluted with ethyl acetate (10 mL)and washed with saturated aqueous NaHCO₃ solution (10 mL). The combinedorganics were dried over sodium sulfate, concentrated and the resultantresidue was purified by column chromatography (SiO₂, 10-12%EtOAc/Hexanes) to afford 200 mg (47% yield) of ethyl(E)-3-(3-((1R,3R)-2-(2-fluoro-2-methylpropyl)-3-methyl-2,3,4,9-tetrahydro-1H-pyrido[3,4-b]indol-yl)bicyclo[1.1.1]pentan-1-yl)acrylate.MS (ESI⁺) m/z 425.33 [M+H]⁺.

Step 3

To a stirred solution of ethyl(E)-3-(3-((1R,3R)-2-(2-fluoro-2-methylpropyl)-3-methyl-2,3,4,9-tetrahydro-1H-pyrido[3,4-b]indol-1-yl)bicyclo[1.1.1]pentan-1-yl)acrylate(220 mg, 0.438 mmol) in methanol/THF (1:1, 2 mL) was added 7.5 M aqueousNaOH solution (0.2 mL) at 0° C. The mixture was stirred at 0° C. for 5h. The resulting reaction mixture was concentrated. The residue wasacidified with saturated sodium hydrogen sulfate at 0° C. to pH 5. Theprecipitate was filtered, washed with water and dried to afford 45 mg(22% yield) of(E)-3-(3-((1R,3R)-2-(2-fluoro-2-methylpropyl)-3-methyl-2,3,4,9-tetrahydro-1H-pyrido[3,4-b]indol-1-yl)bicyclo[1.1.1]pentan-1-yl)acrylicacid as an off white solid. ¹H NMR (400 MHz, DMSO-d₆) δ 12.2 (br s 1H),10.5 (s, 1H), 7.35 (d, J=8.0 Hz, 1H), 7.27 (d, J=7.6 Hz, 1H), 7.02 (t,J=7.2 Hz, 1H), 6.93 (t, J=6.8 Hz, 1H), 6.81 (s, J=15.6 Hz, 1H), 5.64 (d,J=15.2 Hz, 1H), 3.88 (s, 1H), 3.32-3.21 (m, 1H), 2.67-2.21 (m, 4H),1.87-1.80 (m, 3H), 1.79-1.77 (m, 3H), 1.41-1.35 (m, 3H), 1.27-1.12 (m,3H), 1.17-1.16 (m, 3H); MS (ESI⁺) m/z 397.34 [M+H]⁺.

Example 1B(E)-3-(3-((1S,3R)-2-(2-Fluoro-2-methylpropyl)-3-methyl-2,3,4,9-tetrahydro-1H-pyrido[3,4-b]indol-1-yl)bicyclo[1.1.1]pentan-1-yl)acrylicacid (1B)

Step 1

To a stirred solution of (R)-1-(1H-indol-3-yl)propan-2-amine (300 mg,1.72 mmol) and ethyl (E)-3-(3-formylbicyclo[1.1.1]pentan-1-yl)acrylate(334 mg, 1.72 mmol) in toluene (5 mL) was added acetic acid (220 mg,3.34 mmol) followed by stirring at 90° C. for 5 h. The reaction mixturewas diluted with ethyl acetate (50 mL) and washed with saturated aqueousNaHCO₃ solution (30 mL). The combined organic layer was dried oversodium sulfate, filtered and concentrated. The residue was purified bycolumn chromatography (SiO₂, 5-7% MeOH in DCM) to afford 350 mg (74%yield) of ethyl(E)-3-(3-((3R)-3-methyl-2,3,4,9-tetrahydro-1H-pyrido[3,4-b]indol-1-yl)bicyclo[1.1.1]pentan-1-yl)acrylateas a 1.2:1.0 mixture of trans/cis isomers. MS (ESI) m/z 351.23 [M+H]⁺.

Step 2

To a stirred solution of ethyl(E)-3-(3-((3R)-3-methyl-2,3,4,9-tetrahydro-1H-pyrido[3,4-b]indol-1-yl)bicyclo[1.1.1]pentan-1-yl)acrylate(0.35 g, 1 mmol) in dioxane (10 mL) was added 2-fluoro-2-methylpropyltrifluoromethanesulfonate (0.246 g, 1.1 mmol), N,N-diisopropylethylamine(258 mg, 17.4 mmol) and potassium iodide. The reaction was stirred at130° C. for 4 h in a microwave oven and then diluted with ethyl acetate(50 mL). The combined organics were dried over sodium sulfate andconcentrated. The resultant residue was purified by columnchromatography (SiO₂, using 45-50% ethyl acetate in pet-ether) to afford0.26 g (61% yield) of ethyl(E)-3-(3-((3R)-2-(2-fluoro-2-methylpropyl)-3-methyl-2,3,4,9-tetrahydro-1H-pyrido[3,4-b]indol-1-yl)bicyclo[1.1.1]pentan-1-yl)acrylate.MS (ESI) m/z 425.2 [M+H]⁺.

Step 3

To a stirred solution of ethyl(E)-3-(3-((3R)-2-(2-fluoro-2-methylpropyl)-3-methyl-2,3,4,9-tetrahydro-1H-pyrido[3,4-b]indol-1-yl)bicyclo[1.1.1]pentan-1-yl)acrylate(250 mg, 0.587 mmol) in methanol (0.6 mL) and THF (0.6 ml) was added 7.5M aqueous NaOH (94 mg 2.35 mmol) solution at 0° C. and stirred at rt for18 h. The reaction mixture was concentrated under reduced pressure. Theobtained residue was acidified with 1N HCl at 0° C., extracted withethyl acetate (3×50 mL) and the combined organic layers were dried overNa₂SO₄, filtered and evaporated under reduced pressure. The obtainedresidue was purified by SFC (Column/dimensions: Chiralcel OJ-H (250×4.6mm), 5 m; % CO₂: 60.0; % Co-solvent: 40.0 (100% Methanol); Total Flow:70.0 g/min; Back Pressure: 100.0 bar; UV: 228 nm; Stack time: 6.5 min;Load/Inj: 11 mg; Solubility: Methanol; Total No of injections: 25;Instrument details: Make/Model: Thar SFC-80) to afford 42 mg (18% yield)of(E)-3-(3-((1S,3R)-2-(2-fluoro-2-methylpropyl)-3-methyl-2,3,4,9-tetrahydro-1H-pyrido[3,4-b]indol-1-yl)bicyclo[1.1.1]pentan-1-yl)acrylicacid as an off white solid. ¹H NMR (400 MHz, DMSO-d₆) δ=12.4-11.8 (br s,1H), 10.3 (s, 1H), 7.36 (d, J=12.4 Hz, 1H), 7.34 (d, J=12.4 Hz, 1H),7.10-6.90 (m, 2H), 6.80 (d, J=15.2 Hz, 1H), 5.65 (d, J=15.2 Hz, 1H),3.91 (s, 1H), 3.31-3.15 (m, 1H), 2.95-2.65 (m, 3H), 2.37 (d, J=14.8 Hz,1H), 1.93 (d, J=9.2 Hz, 3H), 1.84 (d, J=9.6 Hz, 3H), 1.45-1.22 (m, 6H),1.10 (d, J=6.8 Hz, 3H); MS (ESI) m/z 397.34 [M+H]⁺.

Example 2A(E)-3-(4-((1R,3R)-2-((3,3-Difluorocyclobutyl)methyl)-3-methyl-2,3,4,9-tetrahydro-1H-pyrido[3,4-b]indol-1-yl)-3,5-difluorophenyl)acrylicacid (2A)

Step 1

4-Bromo-2,6-difluorobenzaldehyde (3 g, 13.6 mmol) and methyl acrylate(1.84 mL, 20.4 mmol) were dissolved in thoroughly degassedN,N-dimethylacetamide. Tri-o-tolylphosphine (0.413 g, 1.36 mmol),palladium(II) acetate (0.152 g, 0.678 mmol) and triethylamine (3.7 mL,27.1 mmol) were added and the reaction was stirred at 80° C. for 6 h.The reaction mixture was cooled, filtered through a Celite pad which waswashed with methanol (20 mL). The filtrate was concentrated underreduced pressure. The crude compound was purified by columnchromatography (SiO₂, 10% EtOAc/Hexanes) to afford 2.5 g (81% Yield) ofmethyl (E)-3-(3,5-difluoro-4-formylphenyl)acrylate as a pale yellowsolid. MS (ESI) m/z 227.08 [M+H]⁺.

Step 2

To a stirred suspension of 3,3-difluorocyclobutanecarboxylic acid (781mg, 5.75 mmol) in dry THF (20 mL) was added propylphosphonic anhydride(10.4 mL, 17.2 mmol, 50% wt/wt in EtOAc) and DIPEA (3 mL, 17.2 mmol) at0° C. The mixture was stirred for 20 min at the same temperaturefollowed by the addition of (R)-1-(1H-indol-3-yl)propan-2-amine (1 g,5.75 mmol) at 0° C. and the reaction was stirred for 16 h at roomtemperature. The reaction mixture was diluted with ice cold water andextracted with EtOAc (2×50 mL). The combined organic layer was driedover Na₂SO₄, filtered and evaporated under reduced pressure. The crudeproduct was purified by flash column chromatography (SiO₂, 20%EtOAc/Hexane) to give 1.2 g (72% yield) of(R)—N-(1-(1H-indol-3-yl)propan-2-yl)-3,3-difluorocyclobutane-1-carboxamideas a light brown solid. MS (ESI) m/z 293 [M+H]⁺.

Step 3

To a stirred suspension of(R)—N-(1-(1H-indol-3-yl)propan-2-yl)-3,3-difluorocyclobutane-1-carboxamide(1.24 g, 4.11 mmol) in dry THF (30 mL) was added LAH (780 mg, 20.5 mmol)portion wise at 0° C. and the reaction was then stirred at reflux for 14h. The reaction mixture was quenched with ice cold water (50 mL) andextracted with EtOAc (2×50 mL). The combined organics were dried overNa₂SO₄, filtered and evaporated under reduced pressure to afford thecrude material which was purified by flash column chromatography (SiO₂,80% EtOAc/Hexane) to provide 1 g (88% yield) of(R)—N-((3,3-difluorocyclobutyl)methyl)-1-(1H-indol-3-yl)propan-2-amineas an off white solid. MS (ESI) m/z 279 [M+H]⁺.

Step 4

To a stirred solution of(R)—N-((3,3-difluorocyclobutyl)methyl)-1-(1H-indol-3-yl)propan-2-amine(800 mg, 2.88 mmol) in toluene (8 mL) was added methyl(E)-3-(3,5-difluoro-4-formylphenyl)acrylate (650 mg, 2.88 mmol) andacetic acid (345 mg, 5.76 mmol). The resulting mixture was stirred at90° C. for 5 h. The reaction mixture was diluted with water andextracted with ethyl acetate (2×50 mL). The combined organic layer wasdried over Na₂SO₄, filtered and evaporated under reduced pressure toafford 800 mg (57% yield) of crude methyl(E)-3-(4-((1R,3R)-2-((3,3-difluorocyclobutyl)methyl)-3-methyl-2,3,4,9-tetrahydro-1H-pyrido[3,4-b]indol-1-yl)-3,5-difluorophenyl)acrylateas a yellow solid which was used without further purification(cis/trans: 1:8); MS (ESI) m/z 487.2 [M+H]⁺.

Step 5

To a stirred solution of methyl(E)-3-(4-((1R,3R)-2-((3,3-difluorocyclobutyl)methyl)-3-methyl-2,3,4,9-tetrahydro-1H-pyrido[3,4-b]indol-1-yl)-3,5-difluorophenyl)acrylate(230 mg, 0.473 mmol) in THF:methanol (5 mL, 4:1) was added a 7.5Maqueous solution of NaOH (56 mg 1.42 mmol) at 0° C. and the mixture wasstirred at rt for 5 h. The reaction mixture was concentrated underreduced pressure to remove methanol. The obtained residue was acidifiedwith 1N HCl at 0° C. The reaction mixture was diluted with EtOAc andwashed with water. The combined organics were dried over sodium sulfateand concentrated to provide the crude product which was purified bypreparative SFC to afford 95 mg (42% yield) of(E)-3-(4-((1R,3R)-2-((3,3-difluorocyclobutyl)methyl)-3-methyl-2,3,4,9-tetrahydro-1H-pyrido[3,4-b]indol-1-yl)-3,5-difluorophenyl)acrylicacid as off white solid. ¹H NMR (300 MHz, DMSO-d₆) δ 10.59 (s, 1H),7.60-7.39 (m, 4H), 7.19 (d, J=7.5 Hz, 1H), 7.08-6.90 (m, 2H), 6.67 (d,J=15.9 Hz, 1H), 5.14 (s, 1H), 3.50-3.16 (m, 1H), 2.90-2.70 (m, 2H),2.63-2.46 (m, 3H), 2.46-2.25 (m, 2H), 2.22-2.15 (m, 1H), 2.05-1.82 (m,1H), 1.06 (d, J=6.0, 3H); MS (ESI) m/z 473.2 [M+H]⁺. [α]_(D)=−79.2° (c0.25, CHCl₃).

Example 3A(E)-3-(3,5-Difluoro-4-((1R,3R)-3-methyl-2-((3-(trifluoromethyl)bicyclo[1.1.1]pentan-1-yl)methyl)-2,3,4,9-tetrahydro-1H-pyrido[3,4-b]indol-1-yl)phenyl)acrylicacid (3A)

Step 1

To a stirred suspension of (R)-1-(1H-indol-3-yl)propan-2-amine (200 mg,1.11 mmol) in dry THF (4 mL) was added propylphosphonic anhydride (2 mL,3.35 mmol, 50% wt/wt in EtOAc) and DIPEA (0.6 mL, 3.35 mmol) at 0° C.The mixture was stirred for 20 min at 0° C. and then3-(trifluoromethyl)bicyclo[1.1.1]pentane-1-carboxylic acid (213 mg, 1.22mmol) was added at 0° C. The reaction was allowed to stir at rt for 16h. The reaction mixture was diluted with ice cold water and extractedwith ethyl acetate (2×50 mL). The combined organic layers were driedover sodium sulfate, filtered and concentrated. The resultant residuewas purified by flash column chromatography (SiO₂, 20% EtOAc/Hexane) toafford 200 mg (64% yield) of(R)—N-(1-(1H-indol-3-yl)propan-2-yl)-3-(trifluoromethyl)bicyclo[1.1.1]pentane-1-carboxamideas a pale brown solid. MS (ESI) m/z; 337.36 [M+H]⁺.

Step 2

To a stirred suspension of(R)—N-(1-(1H-indol-3-yl)propan-2-yl)-3-(trifluoromethyl)bicyclo[1.1.1]pentane-1-carboxamide(200 mg, 0.595 mmol) in dry THF (5 mL) was added LAH (135 mg, 3.57 mmol)portionwise at 0° C. and the mixture was heated at reflux for 14 h. Icewater (50 mL) was added and the mixture was extracted with EtOAc (2×50mL). The combined organic layer was dried over sodium sulfate, filteredand concentrated. The resultant residue was purified by flash columnchromatography (SiO₂, 80% EtOAc/Hexane) to afford 150 mg (78% yield) of(R)-1-(1H-indol-3-yl)-N-((3-(trifluoromethyl)bicyclo[1.1.1]pentan-1-yl)methyl)propan-2-amineas an off white solid. MS (ESI) m/z 323.23 [M+H]⁺.

Step 3

To a stirred solution of(R)-1-(1H-indol-3-yl)-N-((3-(trifluoromethyl)bicyclo[1.1.1]pentan-1-yl)methyl)propan-2-amine(150 mg, 0.465 mmol) in toluene (3 mL) was added methyl(E)-3-(3,5-difluoro-4-formylphenyl)acrylate (126 mg, 0.55 mmol) andacetic acid (55 mg, 0.931 mmol). The resulting mixture was stirred at90° C. for 5 h. The reaction mixture was diluted with water andextracted with ethyl acetate (2×50 mL). The combined organics were driedover Na₂SO₄, filtered and evaporated under reduced pressure to affordthe crude product which was purified by flash column chromatography(SiO₂, 15% EtOAc/hexane) to afford 140 mg (56% yield) of methyl(E)-3-(3,5-difluoro-4-((1R,3R)-3-methyl-2-((3-(trifluoromethyl)bicyclo[1.1.1]pentan-1-yl)methyl)-2,3,4,9-tetrahydro-1H-pyrido[3,4-b]indol-1-yl)phenyl)acrylateas an off white solid. MS (ESI) m/z 531.35 [M+H]⁺.

Step 4

To a stirred solution of methyl(E)-3-(3,5-difluoro-4-((1R,3R)-3-methyl-2-((3-(trifluoromethyl)bicyclo[1.1.1]pentan-1-yl)methyl)-2,3,4,9-tetrahydro-1H-pyrido[3,4-b]indol-1-yl)phenyl)acrylate(140 mg, 0.26 mmol) in THF:methanol (5 mL, 4:1) was added 7.5 M aqueousNaOH (0.10 mL, 0.79 mmol) solution at 0° C. and the mixture was stirredat rt for 5 h. Concentration afforded a residue which was acidified with1N HCl at 0° C. and extracted with EtOAc (3×50 mL). The combinedorganics were dried over Na₂SO₄, filtered and evaporated under reducedpressure. The crude product was further purified by SFC to afford 50 mg(37% yield) of(E)-3-(3,5-difluoro-4-((1R,3R)-3-methyl-2-((3-(trifluoromethyl)bicyclo[1.1.1]pentan-1-yl)methyl)-2,3,4,9-tetrahydro-1H-pyrido[3,4-b]indol-1-yl)phenyl)acrylicacid as a pale yellow solid. ¹H NMR (400 MHz, DMSO-d₆) δ 12.58 (br s1H), 10.55 (s 1H), 7.53 (d, J=16 Hz, 1H), 7.48 (d, J=10.8 Hz, 2H), 7.41(d, J=7.8 Hz, 1H), 7.18 (d, J=7.8 Hz, 1H), 7.02-6.92 (m, 2H), 6.68 (d,J=15.9 Hz, 1H), 5.12 (s, 1H), 3.42-3.28 (m, 1H), 2.95 (dd, J=14.7 Hz,4.2 Hz, 1H), 2.83 (d, J=14.4 Hz, 1H), 2.59 (d, J=16.8 Hz, 1H), 2.37 (d,J=14.4 Hz, 1H), 1.75 (d, J=9.3 Hz, 3H), 1.63 (d, J=9.3 Hz, 3H), 1.07 (d,J=6 Hz, 3H); MS (ESI) m/z 517.32 [M+H]⁺. [α]_(D)=−70.0° (c=0.5, MeOH,25° C.).

Examples 4A and 4B(E)-3-(3,5-Difluoro-4-((1R,3R)-3-methyl-2-(3-(trifluoromethyl)bicyclo[1.1.1]pentan-1-yl)-2,3,4,9-tetrahydro-1H-pyrido[3,4-b]indol-1-yl)phenyl)acrylicacid (4A)

(E)-3-(3,5-Difluoro-4-((1S,3S)-3-methyl-2-(3-(trifluoromethyl)bicyclo[1.1.1]pentan-1-yl)-2,3,4,9-tetrahydro-1H-pyrido[3,4-b]indol-1-yl)phenyl)acrylicacid (4B)

Step 1

To a stirred solution of 1-(1H-indol-3-yl)propan-2-one (0.400 g, 2.31mmol) in methanol (3 mL) was added3-(trifluoromethyl)bicyclo[1.1.1]pentan-1-amine (0.518 g, 2.77 mmol) andacetic acid (14 mg, 0.231 mmol) and the mixture was stirred at rt for 16hours. The resulting solution was cooled to 0° C. and sodiumcyanoborohydride (0.290 g, 4.62 mmol) was added followed by additionalstirring for 5 h at rt. The reaction was diluted with ethyl acetate (10mL) and washed with saturated, aqueous NH₄Cl solution (10 mL). Thecombined organic layer was dried over sodium sulfate, filtered andconcentrated. The crude residue was purified by column chromatographyusing (SiO₂, 15% EtOAc/Hexane) to afford 0.4 g ofN-(1-(1H-indol-3-yl)propan-2-yl)-3-(trifluoromethyl)bicyclo[1.1.1]pentan-1-aminewhich was used without further purification; MS (ESI) m/z 309.18 [M+H]⁺.

Step 2

To a stirred solution ofN-(1-(1H-indol-3-yl)propan-2-yl)-3-(trifluoromethyl)bicyclo[1.1.1]pentan-1-amine(1.2 g, 3.90 mmol) in toluene (6 mL) was added methyl(E)-3-(3,5-difluoro-4-formylphenyl)acrylate (0.880 g, 3.90 mmol) andacetic acid (0.467 g, 7.79 mmol). The resulting mixture was stirred at90° C. for 5 h. The reaction mixture was diluted with EtOAc and washedwith water. The combined organic phase was dried over sodium sulfate,filtered and concentrated. The residue was purified by chiral SFC(Chiralcel OD-H (5 μm, 250×21 mm) % CO₂: 85.0%, % Co-solvent (EtOH):15.0%; Total Flow: 60.0 g/min; Back Pressure: 100.0 bar; UV: 220 nm;Stack time: 5.5 min; Load/Inj: 2.8 mg; Solubility: MeOH; Total number ofinjections: 35; Instrument details: Make/Model: Thar SFC-80) to afford180 mg (9% yield) of methyl(E)-3-(3,5-difluoro-4-((1R,3R)-3-methyl-2-(3-(trifluoromethyl)bicyclo[1.1.1]pentan-1-yl)-2,3,4,9-tetrahydro-1H-pyrido[3,4-b]indol-1-yl)phenyl)acrylate(designated as PEAK-1) and 180 mg (9% yield) of methyl(E)-3-(3,5-difluoro-4-((1S,3S)-3-methyl-2-(3-(trifluoromethyl)bicyclo[1.1.1]pentan-1-yl)-2,3,4,9-tetrahydro-1H-pyrido[3,4-b]indol-1-yl)phenyl)acrylate(designated as PEAK-2). Methyl(E)-3-(3,5-difluoro-4-((1R,3R)-3-methyl-2-(3-(trifluoromethyl)bicyclo[1.1.1]pentan-1-yl)-2,3,4,9-tetrahydro-1H-pyrido[3,4-b]indol-1-yl)phenyl)acrylate:MS (ESI) m/z 517.18 [M+H]⁺. Methyl(E)-3-(3,5-difluoro-4-((1S,3S)-3-methyl-2-(3-(trifluoromethyl)bicyclo[1.1.1]pentan-1-yl)-2,3,4,9-tetrahydro-1H-pyrido[3,4-b]indol-1-yl)phenyl)acrylate:MS (ESI) m/z 517.18 [M+H]⁺. Note: absolute stereochemistry arbitrarilyassigned.

Step 3-a

To a stirred solution of methyl(E)-3-(3,5-difluoro-4-((1R,3R)-3-methyl-2-(3-(trifluoromethyl)bicyclo[1.1.1]pentan-1-yl)-2,3,4,9-tetrahydro-1H-pyrido[3,4-b]indol-1-yl)phenyl)acrylate(180 mg, 0.349 mmol) in methanol (1.5 mL) was added aqueous solution ofNaOH (0.13 mL, 0.039 g, 0.988 mmol, 7.5M) at 0° C. and the mixture wasstirred at rt for 5 h. The reaction mixture was concentrated underreduced pressure to remove methanol. The residue was acidified with 1NHCl at 0° C., diluted with EtOAc and washed with water. The combinedorganic layer was dried over sodium sulfate, filtered and concentrated.The crude residue was purified by SFC (Chiralcel OJ-H (5 μm, 250×21 mm);% CO₂: 50.0%; % Co-solvent (EtOH): 50.0%; Total Flow: 60.0 g/min; BackPressure: 90.0 bar; UV: 220 nm; Stack time: 6.5 min; Load/Inj: 36 mg;Solubility: MeOH; Total Number of injections: 6; Instrument details:Make/Model: Thar SFC-80) to afford 90 mg (55% yield) of(E)-3-(3,5-difluoro-4-((1R,3R)-3-methyl-2-(3-(trifluoromethyl)bicyclo[1.1.1]pentan-1-yl)-2,3,4,9-tetrahydro-1H-pyrido[3,4-b]indol-1-yl)phenyl)acrylicacid as an off white solid. ¹H NMR (300 MHz, DMSO-d₆) δ 10.6 (br s, 1H),7.62-7.39 (m, 4H), 7.18 (d, J=7.5 Hz, 1H), 7.03-6.92 (m, J=7.2 Hz, 2H),6.68 (d, J=16.2 Hz, 1H), 5.38 (s, 1H), 3.62 (br s, 1H), 3.05-2.97 (m,1H), 2.63-2.58 (m, 1H), 2.08-1.79 (m 6H), 1.09 (d, J=6 Hz, 3H); MS (ESI)m/z 503.26 [M+H]⁺. [α]_(D)=−58.4° (c 0.25, CHCl₃, 24° C.).

Step 3-b

To a stirred solution of methyl(E)-3-(3,5-difluoro-4-((1S,3S)-3-methyl-2-(3-(trifluoromethyl)bicyclo[1.1.1]pentan-1-yl)-2,3,4,9-tetrahydro-1H-pyrido[3,4-b]indol-1-yl)phenyl)acrylate(170 mg, 0.329 mmol) in methanol (1.5 mL) was added aqueous NaOH (0.13mL, 0.988 mmol, 7.5M) at 0° C. and the reaction was stirred at rt for 5h. The reaction mixture was concentrated under reduced pressure toremove methanol. The residue was acidified with 1N HCl at 0° C. thendiluted with EtOAc and washed with water. The combined organic layer wasdried over sodium sulfate, filtered and concentrated. The crude residuewas purified by SFC (Chiralcel OJ-H (5 am, 250×21 mm); % CO₂: 55.0; %Co-solvent (EtOH): 45.0; Total Flow: 60.0 g/min; Back Pressure: 90.0bar; UV: 220 nm; Stack time: 6.8 min; Load/Inj: 12 mg; Solubility: MeOH;Total No of injections: 15; Instrument details: Make/Model: Thar SFC-80)to afford 115 mg (70% yield) of(E)-3-(3,5-difluoro-4-((1S,3S)-3-methyl-2-(3-(trifluoromethyl)bicyclo[1.1.1]pentan-1-yl)-2,3,4,9-tetrahydro-1H-pyrido[3,4-b]indol-1-yl)phenyl)acrylicacid as an off white solid. ¹H NMR (300 MHz, DMSO-d₆) δ 10.6 (br s, 1H),7.62-7.39 (m, 4H), 7.18 (d, J=7.8 Hz, 1H), 7.03-6.92 (m, 2H), 6.68 (d,J=15.2 Hz, 1H), 5.39 (s, 1H), 3.62 (br s, 1H), 3.01-2.95 (m, 1H)2.63-2.58 (m, 1H), 2.12-1.72 (m, 6H), 1.09 (d, J=6.0 Hz, 3H); MS (ESI):m/z 503.26 [M+H]⁺. [α]_(D) +42.4 (c 0.25, CHCl₃, 24° C.).

Compounds 4A and 4B are shown above and in Table 1 with absolutestereochemistry arbitrarily assigned.

Example 5A(E)-3-(4-((1R,3R)-2-(Bicyclo[1.1.1]pentan-1-ylmethyl)-3-methyl-2,3,4,9-tetrahydro-1H-pyrido[3,4-b]indol-1-yl)-3,5-difluorophenyl)acrylicacid (5A)

Step 1

To a stirred solution of (R)-1-(1H-indol-3-yl)propan-2-amine (0.500 g,2.87 mmol) in THF (10 mL) was added propylphosphonic anhydride (2.25 mL,8.60 mmol, 50% wt/wt in EtOAc) and N,N-diisopropylethylamine (1.5 mL,8.60 mmol) at rt. The solution was stirred for 10 minutes and then asolution of bicyclo[1.1.1]pentane-1-carboxylic acid (0.375 g, 3.16 mmol)was added and the mixture was stirred at rt for an additional 16 h.Water (3 mL) was added and the reaction mixture was extracted with EtOAc(2×50 mL). The combined organic layers were dried over Na₂SO₄, filteredand evaporated under reduced pressure. The crude product was trituratedwith ether to obtain 700 mg (90% yield) of(R)—N-(1-(1H-indol-3-yl)propan-2-yl)bicyclo[1.1.1]pentane-1-carboxamideof the formula

as a pale yellow solid. MS (ESI) m/z 269.26 [M+H]⁺.

Step 2

To a stirred solution of(R)—N-(1-(1H-indol-3-yl)propan-2-yl)bicyclo[1.1.1]pentane-1-carboxamide(700 mg, 2.61 mmol) in THF (10 mL) was added LAH (600 mg, 15.7 mmol)portion wise at 0° C. The mixture was heated to reflux for 16 h, cooledto rt and then slowly treated with ice water (50 mL) and extracted withEtOAc (2×50 mL). The combined organic layer was dried over Na₂SO₄,filtered and concentrated under reduced pressure. The crude residue wastriturated with ether to obtain 600 mg (90% yield) of semi-pure(R)—N-(bicyclo[1.1.1]pentan-1-ylmethyl)-1-(1H-indol-3-yl)propan-2-amineof the formula

as a pale yellow solid. MS (ESI) m/z 255.36 [M+H]⁺.

Step 3

To a stirred solution of semi-pure(R)—N-(bicyclo[1.1.1]pentan-1-ylmethyl)-1-(1H-indol-3-yl)propan-2-amine(600 mg, 2.36 mmol) in toluene (12 mL), methyl(E)-3-(3,5-difluoro-4-formylphenyl)acrylate (540 mg, 2.36 mmol) andacetic acid (285 mg, 4.7 mmol) were added and the mixture was stirred at90° C. for 12 h. The reaction mixture was neutralized with a saturatedaqueous solution of sodium bicarbonate then extracted with EtOAc (2×50mL). The combined organic layer was dried over Na₂SO₄, filtered andevaporated under reduced pressure to afford 400 mg (36% yield) of crudemethyl(E)-3-(4-((1R,3R)-2-(bicyclo[1.1.1]pentan-1-ylmethyl)-3-methyl-2,3,4,9-tetrahydro-1H-pyrido[3,4-b]indol-1-yl)-3,5-difluorophenyl)acrylateas a mixture of cis/trans isomers. MS (ESI) m/z 463.38 [M+H]⁺.

Step 4

To a stirred solution of methyl(E)-3-(4-((1R,3R)-2-(bicyclo[1.1.1]pentan-1-ylmethyl)-3-methyl-2,3,4,9-tetrahydro-1H-pyrido[3,4-b]indol-1-yl)-3,5-difluorophenyl)acrylate(400 mg of a mixture of cis/trans isomers, 0.86 mmol) in a mixture ofTHF/MeOH (6 mL, 5:1) was added an aqueous solution of NaOH (0.5 mL,1.5M) at 0° C. and the mixture was stirred at rt for 16 h. Standardaqueous work-up and SFC purification provided 140 mg (Yield 37%) of(E)-3-(4-((1R,3R)-2-(bicyclo[1.1.1]pentan-1-ylmethyl)-3-methyl-2,3,4,9-tetrahydro-1H-pyrido[3,4-b]indol-1-yl)-3,5-difluorophenyl)acrylicacid as pale yellow solid: ¹H NMR (400 MHz, DMSO-d₆) δ 12.50 (br s 1H),10.50 (s, 1H), 7.55 (d, J=16.0 Hz, 1H), 7.46 (d, J=8 Hz, 2H), 7.39 (d,J=8 Hz, 1H), 7.16 (d, J=8 Hz, 1H), 6.99 (dd, J=7.6 Hz, 6.8 Hz, 1H), 6.94(dd, J=7.6 Hz, 7.2 Hz, 1H), 6.67 (d, J=16 Hz, 1H), 5.08 (s, 1H),3.45-3.56 (m, 1H), 2.94 (dd, J=12.8 Hz, 4 Hz, 1H), 2.68 (d, J=14 Hz,1H), 2.56 (dd, J=12 Hz, 0.9 Hz, 1H), 2.37 (s, 1H), 2.24 (d, J=14.8 Hz,1H), 1.56 (d, J=8.8 Hz, 3H), 1.46 (d, J=9.2 Hz, 3H), 1.00 (d, J=6.4 Hz,3H); MS (ESI) m/z 449.39 [M+H]⁺, [α]_(D) +65.6° (c 0.25, MeOH, 24° C.).

Example 6A(E)-3-(3,5-Difluoro-4-((1R,3R)-3-methyl-2-(tetrahydro-2H-pyran-4-yl)-2,3,4,9-tetrahydro-1H-pyrido[3,4-b]indol-1-yl)phenyl)acrylicacid (6A)

Step 1

To a stirred solution of (R)-1-(1H-indol-3-yl)propan-2-amine (0.5 g,2.86 mmol) in ethanol (3 mL) was added tetrahydro-4H-furan-4 one (0.27 g2.86 mmol) and the mixture was heated to 80° C. for 3 h. The resultingreaction mixture was cooled to 0° C. and sodium borohydride (0.216 g,5.72 mmol) was added. The mixture was stirred at rt for 2 h and thendiluted with ethyl acetate (10 mL) and washed with saturated aqueousNH₄Cl solution (10 mL) followed by brine. The combined organic layerswere dried over sodium sulfate and concentrated under reduced pressureto afford 0.61 g (82% yield) of(R)—N-(1-(1H-indol-3-yl)propan-2-yl)tetrahydro-2H-pyran-4-amine as acolorless gummy liquid. MS (ESI) m/z 259.18 [M+H]⁺.

Step 2

To a stirred solution ofN-(1-(1H-indol-3-yl)propan-2-yl)tetrahydro-2H-pyran-4-amine (0.5 g, 1.93mmol) in 5 mL of toluene was added methyl(E)-3-(3,5-difluoro-4-formylphenyl)acrylate (0.437 g, 1.94 mmol) andacetic acid (232 mg, 3.87 mmol). The resulting mixture was stirred at90° C. for 5 h. The reaction mixture was diluted with EtOAc, washed withwater, dried over sodium sulfate and concentrated under reduced pressureto afford 220 mg (24% yield) of methyl(E)-3-(3,5-difluoro-4-((1R,3R)-3-methyl-2-(tetrahydro-2H-pyran-4-yl)-2,3,4,9-tetrahydro-1H-pyrido[3,4-b]indol-1-yl)phenyl)acrylateas a pale yellow solid. MS (ESI) m/z 467.31 [M+H]⁺.

Step 3

To a stirred solution of methyl(E)-3-(3,5-difluoro-4-((1R,3R)-3-methyl-2-(tetrahydro-2H-pyran-4-yl)-2,3,4,9-tetrahydro-1H-pyrido[3,4-b]indol-1-yl)phenyl)acrylate(220 mg, 0.398 mmol) in methanol (2 mL) was added an aqueous solution ofNaOH (0.159 mL, 1.19 mmol, 7.5M) solution at 0° C. and stirred at rt for4 h. The reaction mixture was concentrated under reduced pressure andthe residue was acidified with 1N HCl at 0° C. The mixture was extractedwith ethyl acetate (3×50 mL) and the combined organic layers were driedover Na₂SO₄, filtered and evaporated under reduced pressure. The crudeproduct was purified by SFC (Column/dimensions: (R,R)-Whelk-01 (5 μm,250×30 mm); % CO₂: 60.0; % co-solvent (IPA): 40.0; total flow: 70.0g/min; Back Pressure: 100.0 bar; UV: 224 nm; Stack time: 5.8 min;Load/Inj: 4.2 mg; Solubility: Methanol; Total No of injections: 35;Instrument details: Make/Model: Thar SFC-80) to afford 80 mg (Yield:46%) of(E)-3-(3,5-difluoro-4-((1R,3R)-3-methyl-2-(tetrahydro-2H-pyran-4-yl)-2,3,4,9-tetrahydro-1H-pyrido[3,4-b]indol-1-yl)phenyl)acrylicacid as an off white solid. ¹H NMR (400 MHz, DMSO-d₆) δ 12.50 (br s 1H),10.56 (br s 1H), 7.55-7.36 (m, 4H), 7.19 (d, J=8 Hz, 1H), 7.00-6.90 (m.2H), 6.65 (d, J=16.4 Hz, 1H), 5.50 (s, 1H), 3.89-3.70 (m, 2H), 3.60-3.52(m, 1H), 3.23-3.12 (m, 2H), 2.94-2.78 (m, 2H), 2.57-2.51 (m, 1H),1.75-1.50 (m, 3H), 1.34-1.15 (m, 4H); MS (ESI) m/z 453.25 [M+H]⁺,[t]_(D)=−80.0° (c 0.25, MeOH, 24° C.).

Example 7A(E)-3-(3,5-Difluoro-4-((1R,3R)-3-methyl-2-(oxetan-3-yl)-2,3,4,9-tetrahydro-1H-pyrido[3,4-b]indol-1-yl)phenyl)acrylicacid (7A)

Step 1

To a stirred solution of (R)-1-(1H-indol-3-yl)propan-2-amine (0.8 g,4.60 mmol) in 3 mL of ethanol was added oxetane-3-one (0.397 g 5.52mmol) and reaction mixture was stirred at 50° C. for 3 hours. Theresulting reaction mixture was cooled to 0° C., treated with sodiumborohydride (0.262 g, 6.90 mmol) and stirred for 5 h at roomtemperature. The mixture was diluted with ethyl acetate (10 mL) andwashed with saturated aqueous NH₄Cl solution (10 mL). The combinedorganic layers were dried over sodium sulfate and concentrated. Thecrude residue was purified by column chromatography (SiO₂, 2-3%methanol/DCM) to afford 0.3 g (28% Yield) of(R)—N-(1-(1H-indol-3-yl)propan-2-yl)oxetan-3-amine as a colorless, gummyliquid. MS (ESI) m/z 231.17 [M+H]⁺.

Step 2

To a stirred solution of(R)—N-(1-(1H-indol-3-yl)propan-2-yl)oxetan-3-amine (0.300 g, 1.30 mmol)in toluene (3 mL) was added methyl(E)-3-(3,5-difluoro-4-formylphenyl)acrylate (0.353 g, 1.56 mmol) andacetic acid (0.156, 2.61 mmol). The resulting mixture was stirred at 90°C. for 5 h. The reaction mixture was diluted with EtOAc and washed withwater. The combined organics were dried over sodium sulfate andconcentrated. The residue was purified by reversed phase prep-HPLC toafford 180 mg (32% Yield) of methyl(E)-3-(3,5-difluoro-4-((1R,3R)-3-methyl-2-(oxetan-3-yl)-2,3,4,9-tetrahydro-1H-pyrido[3,4-b]indol-1-yl)phenyl)acrylateas a pale yellow solid. MS (ESI) m/z 439.24 [M+H]⁺.

Step 3

To a stirred solution of methyl(E)-3-(3,5-difluoro-4-((1R,3R)-3-methyl-2-(oxetan-3-yl)-2,3,4,9-tetrahydro-1H-pyrido[3,4-b]indol-1-yl)phenyl)acrylate(130 mg, 0.296 mmol) in methanol (1.5 mL) was added an aqueous solutionof NaOH (35 mg, 0.888 mmol, 7.5M) at 0° C. The mixture was stirred at rtfor 5 h. The reaction mixture was concentrated under reduced pressure toremove methanol. The obtained residue was acidified with 1N HCl at 0° C.and then diluted with EtOAc and washed with water. The combined organiclayers were dried over sodium sulfate, filtered and concentrated. Theresidue was triturated with n-pentane to afford 70 mg (56% yield) of(E)-3-(3,5-difluoro-4-((1R,3R)-3-methyl-2-(oxetan-3-yl)-2,3,4,9-tetrahydro-1H-pyrido[3,4-b]indol-1-yl)phenyl)acrylicacid as an off white solid. ¹H NMR (400 MHz, DMSO-d₆) δ 12.6 (br s, 1H),10.6 (br s, 1H), 7.57-7.39 (m, 4H), 7.19 (d, J=7.2 Hz, 1H), 7.02-6.93(m, J=7.2 Hz, 2H), 6.68 (d, J=16 Hz, 1H), 5.12 (s, 1H), 4.63 (br s, 1H),4.52 (br s, 1H), 4.20 (br s, 1H), 3.93 (br s, 2H), 2.93 (d, J=15.2 Hz,1H), 2.56 (br s, 2H), 1.00 (br s, 3H); MS (ESI) m/z 425.29 [M+H]⁺.

Examples 8A and 8B(E)-3-(3,5-Difluoro-4-((1R,3R)-3-methyl-2-((S)-tetrahydrofuran-3-yl)-2,3,4,9-tetrahydro-1H-pyrido[3,4-b]indol-1-yl)phenyl)acrylicacid (8A)

(E)-3-(3,5-Difluoro-4-((1R,3R)-3-methyl-2-((R)-tetrahydrofuran-3-yl)-2,3,4,9-tetrahydro-1H-pyrido[3,4-b]indol-1-yl)phenyl)acrylicacid (8B)

Step 1

To a stirred solution of (R)-1-(1H-indol-3-yl)propan-2-amine (0.8 g,4.60 mmol) in ethanol (3 mL) was added dihydrofuran-3(2H)-one (0.474 g,5.52 mmol) and acetic acid (0.275 g, 4.60 mmol) at rt and stirred for 3hours. The resulting reaction mixture was cooled to 0° C. and treatedwith sodium borohydride (0.262 g, 6.90 mmol) and then stirred for 5 h atrt. The mixture was diluted with ethyl acetate (10 mL) and washed withsaturated aqueous NH₄Cl solution (10 mL). The combined organic layerswere dried over sodium sulfate and concentrated. The obtained residuewas purified by column chromatography (SiO₂, 2-3% MeOH/DCM) to afford0.450 g (40% Yield) ofN—((R)-1-(1H-indol-3-yl)propan-2-yl)tetrahydrofuran-3-amine as acolorless gummy liquid. MS (ESI) m/z 245.21 [M+H]⁺.

Step 2

To a stirred solution ofN—((R)-1-(1H-indol-3-yl)propan-2-yl)tetrahydrofuran-3-amine (0.450 g,1.84 mmol) in toluene (3 mL) was added methyl(E)-3-(3,5-difluoro-4-formylphenyl)acrylate (0.501 g, 2.21 mmol) andacetic acid (0.221 g, 3.68 mmol). The resulting mixture was stirred at90° C. for 5 h. The reaction mixture was diluted with EtOAc, washed withwater, dried over sodium sulfate, filtered and concentrated. The residuewas purified by chiral SFC to afford 150 mg (18% yield) of methyl(E)-3-(3,5-difluoro-4-((1R,3R)-3-methyl-2-((S)-tetrahydrofuran-3-yl)-2,3,4,9-tetrahydro-1H-pyrido[3,4-b]indol-1-yl)phenyl)acrylateand 180 mg (22% yield) of methyl(E)-3-(3,5-difluoro-4-((1R,3R)-3-methyl-2-((R)-tetrahydrofuran-3-yl)-2,3,4,9-tetrahydro-1H-pyrido[3,4-b]indol-1-yl)phenyl)acrylateas pale yellow solids. Methyl(E)-3-(3,5-difluoro-4-((1R,3R)-3-methyl-2-((S)-tetrahydrofuran-3-yl)-2,3,4,9-tetrahydro-1H-pyrido[3,4-b]indol-1-yl)phenyl)acrylate:MS (ESI): m/z 453.24 [M+H]⁺. Methyl(E)-3-(3,5-difluoro-4-((1R,3R)-3-methyl-2-((R)-tetrahydrofuran-3-yl)-2,3,4,9-tetrahydro-1H-pyrido[3,4-b]indol-1-yl)phenyl)acrylate:MS (ESI) m/z 453.25 [M+H]⁺.

Step 3-a

To a stirred solution of methyl(E)-3-(3,5-difluoro-4-((1R,3R)-3-methyl-2-((S)-tetrahydrofuran-3-yl)-2,3,4,9-tetrahydro-1H-pyrido[3,4-b]indol-1-yl)phenyl)acrylate(150 mg, 0.296 mmol) in methanol (1.5 mL) was added an aqueous solutionof NaOH (0.132 mL, 0.995 mmol, 7.5M) at 0° C. and stirred at rt for 5 h.The reaction mixture was concentrated under reduced pressure. Theresidue was acidified with 1N HCl at 0° C., extracted with ethyl acetate(3×50 mL) and the combined organic layers were dried over Na₂SO₄,filtered and evaporated under reduced pressure to afford the crudeproduct. The residue was purified by chiral SFC to afford 40 mg (27%Yield) of(E)-3-(3,5-difluoro-4-((1R,3R)-3-methyl-2-((S)-tetrahydrofuran-3-yl)-2,3,4,9-tetrahydro-1H-pyrido[3,4-b]indol-1-yl)phenyl)acrylicacid as an off white solid. ¹H NMR (300 MHz, DMSO-d₆) δ 10.6 (br s, 1H),7.65-7.34 (m, 4H), 7.19 (d, J=7.5 Hz, 1H), 7.04-6.88 (m, 2H), 6.64 (d,J=15.6 Hz, 1H), 5.29 (s, 1H), 3.79-3.40 (m, 6H), 2.83 (dd, J=15, 4.2 Hz,1H), 2.57 (d, J=6.9 Hz, 1H), 1.69-1.62 (m, 1H), 1.58-1.46 (m, 1H), 1.16(d, J=6.9 Hz, 3H); MS (ESI): m/z 439.26 [M+H]+; [α]_(D)=−73.2° (c 0.25,CHCl₃, 24° C.).

Step 3-b

To a stirred solution of methyl(E)-3-(3,5-difluoro-4-((1R,3R)-3-methyl-2-((R)-tetrahydrofuran-3-yl)-2,3,4,9-tetrahydro-1H-pyrido[3,4-b]indol-1-yl)phenyl)acrylate(0.180 g, 0.398 mmol) in methanol (2 mL) was added an aqueous solutionof NaOH (0.159 mL, 1.19 mmol, 7.5M) at 0° C. and stirred at rt for 5 h.The reaction mixture was concentrated under reduced pressure. Theobtained residue was acidified with 1N HCl at 0° C. and extracted withethyl acetate (3×50 mL). The combined organic layers were dried overNa₂SO₄, filtered and evaporated under reduced pressure to afford thecrude product. The residue was purified by chiral SFC to afford 80 mg(46% Yield) of(E)-3-(3,5-difluoro-4-((1R,3R)-3-methyl-2-((R)-tetrahydrofuran-3-yl)-2,3,4,9-tetrahydro-1H-pyrido[3,4-b]indol-1-yl)phenyl)acrylicacid as an off white solid. ¹H NMR (300 MHz, DMSO-d₆) δ 12.7 (br s, 1H),10.6 (s, 1H), 7.58-7.32 (m, 4H), 7.18 (d, J=8.1 Hz, 1H), 7.02-6.91 (m,2H), 6.66 (d, J=15.6 Hz, 1H), 5.31 (s, 1H), 3.88-3.75 (m, 1H), 3.68-3.48(m, 3H), 3.31-3.22 (m, 1H), 3.08 (t, J=8.1 Hz, 1H), 2.89 (dd, J=15 Hz,3.6 Hz, 1H), 2.54-2.51 (m, 1H), 2.14-1.96 (m, 2H), 1.14 (d, J=6.3 Hz,3H); MS (ESI): m/z 439.26 [M+H]+; [t]_(D)=−70.4° (c 0.25, CHCl₃, 24°C.).

The stereochemistry for compounds 8A and 8B was confirmed withsmall-molecule X-ray crystallography as indicated above and in Table 1.

Examples 9A and 9B(E)-3-(4-((1R,3R)-2-(3,3-Difluorocyclobutyl)-3-methyl-2,3,4,9-tetrahydro-1H-pyrido[3,4-b]indol-1-yl)-3,5-difluorophenyl)acrylicacid (9A)

(E)-3-(4-((1S,3S)-2-(3,3-Difluorocyclobutyl)-3-methyl-2,3,4,9-tetrahydro-1H-pyrido[3,4-b]indol-1-yl)-3,5-difluorophenyl)acrylicacid (9B)

Step 1

To a stirred solution of 1-(1H-indol-3-yl)propan-2-one (2 g, 11.6 mmol)in methanol (10 mL) was added 3,3-difluorocyclobutan-1-aminehydrochloride (1.81 g 12.7 mmol) and acetic acid (0.069 g, 1.15 mmol) atrt. The reaction was stirred for 3 hours, cooled to 0° C. and sodiumcyanoborohydride (1.40 g, 23.1 mmol) was added. The mixture was stirredat rt for 24 h. The reaction was diluted with ethyl acetate (10 mL),washed with saturated aqueous NH₄Cl solution (10 mL) followed by brine.The combined organic layers were dried over sodium sulfate, filtered andconcentrated under reduced pressure. The residue was purified by columnchromatography (SiO₂, 2-3% MeOH/DCM) to afford 2.2 g (72% Yield) ofN-(1-(1H-indol-3-yl)propan-2-yl)-3,3-difluorocyclobutan-1-amine as acolorless gummy liquid. MS (ESI) m/z 265.35 [M+H]⁺.

Step 2

To a stirred solution ofN-(1-(1H-indol-3-yl)propan-2-yl)-3,3-difluorocyclobutan-1-amine (2.2 g,8.33 mmol) in toluene (25 mL) was added methyl(E)-3-(3,5-difluoro-4-formylphenyl)acrylate (2.07 g, 9.16 mmol) andacetic acid (0.1 ml, 1.66 mmol). The resulting mixture was stirred at80° C. for 5 h. The reaction mixture was diluted with EtOAc and washedwith water, dried over sodium sulfate, filtered and concentrated. Theresidue was purified by chiral SFC (Column/dimensions: Chiralpak AD-H (5am, 250×21 mm); % CO₂: 65.0; % co-solvent (EtOH): 35.0; Total Flow: 60.0g/min; Back Pressure: 100.0 bar; UV: 221 nm; Stack time: 5.0 min;Load/Inj: 2.5 mg; Solubility: MeOH; Total No of injections: 60;Instrument details: Make/Model: Thar SFC-80) to afford 500 mg (13%Yield) of methyl(E)-3-(4-((1R,3R)-2-(3,3-difluorocyclobutyl)-3-methyl-2,3,4,9-tetrahydro-1H-pyrido[3,4-b]indol-1-yl)-3,5-difluorophenyl)acrylate(Designated as Peak 1) and 500 mg (13% Yield) of methyl(E)-3-(4-((1S,3S)-2-(3,3-difluorocyclobutyl)-3-methyl-2,3,4,9-tetrahydro-1H-pyrido[3,4-b]indol-1-yl)-3,5-difluorophenyl)acrylate(Designated as Peak 2). Methyl(E)-3-(4-((1R,3R)-2-(3,3-difluorocyclobutyl)-3-methyl-2,3,4,9-tetrahydro-1H-pyrido[3,4-b]indol-1-yl)-3,5-difluorophenyl)acrylate:MS (ESI) m/z 473.26 [M+H]⁺. Methyl (E)-3-(4-((1S,3S)-2-(3,3-difluorocyclobutyl)-3-methyl-2,3,4,9-tetrahydro-1H-pyrido[3,4-b]indol-1-yl)-3,5-difluorophenyl)acrylate:MS (ESI) m/z 473.26 [M+H]⁺.

Step 3-a

To a stirred solution of methyl(E)-3-(4-((1R,3R)-2-(3,3-difluorocyclobutyl)-3-methyl-2,3,4,9-tetrahydro-1H-pyrido[3,4-b]indol-1-yl)-3,5-difluorophenyl)acrylate(0.250 g, 0.520 mmol) in methanol (1.5 mL) was added an aqueous solutionof NaOH (0.14 mL, 1.05 mmol, 7.5M) at 0° C. and the reaction was stirredat rt for 5 h. The reaction mixture was concentrated under reducedpressure. The resulting residue was acidified with 1N HCl at 0° C. andthen extracted ethyl acetate (3×50 mL). The combined organic layers weredried over Na₂SO₄, filtered and evaporated under reduced pressure. Theresidue was purified by chiral SFC [Column/dimensions: Chiralcel OD-H (5am, 250×30 mm); % CO₂: 65.0; % Co-solvent (MeOH): 35.0; Total Flow: 60.0g/min; Back Pressure: 100.0 bar; UV: 223 nm; Stack time: 3.5 min;Load/Inj: 4.0 mg; Solubility: MeOH+DCM; Total Number of injections: 55;instrument details: Make/Model: Thar SFC-80] to afford 130 mg (53%yield) of(E)-3-(4-((1R,3R)-2-(3,3-difluorocyclobutyl)-3-methyl-2,3,4,9-tetrahydro-1H-pyrido[3,4-b]indol-1-yl)-3,5-difluorophenyl)acrylicacid as an off white solid. ¹H NMR (300 MHz, DMSO-d₆) δ 10.6 (s 1H),7.60-7.38 (m, 4H), 7.18 (d, J=7.5 Hz, 1H), 7.08-6.90 (m, 2H), 6.68 (d,J=15.9 Hz, 1H), 5.16 (s, 1H), 3.59-3.42 (m, 1H), 3.40-3.25 (m, 1H), 2.94(dd, J=14.9, 4.0 Hz, 2H), 2.90-2.71 (m, 1H), 2.71-2.56 (m, 1H),2.22-2.05 (m, 1H), 2.00-1.80 (m, 1H), 1.03 (d, J=6.6, 3H); MS (ESI) m/z459.26 [M+H]+; [α]_(D)=−40.0° (c 0.25, MeOH, 24° C.).

Step 3-b

To a stirred solution of methyl(E)-3-(4-((1S,3S)-2-(3,3-difluorocyclobutyl)-3-methyl-2,3,4,9-tetrahydro-1H-pyrido[3,4-b]indol-1-yl)-3,5-difluorophenyl)acrylate(250 mg, 0.525 mmol) in methanol (1.5 mL) was added an aqueous solutionof NaOH (0.14 mL, 1.05 mmol, 7.5M) at 0° C. and the reaction was stirredat rt for 5 h. The mixture was concentrated under reduced pressure toremove solvent. The residue was acidified with 1N HCl solution at 0° C.and then extracted with ethyl acetate (3×50 mL). The combined organiclayer was dried over Na₂SO₄, filtered and evaporated under reducedpressure. The residue was purified by chiral SFC [Column/dimensions:Chiralcel OD-H (5 am, 250×30 mm); % CO₂: 60.0; % Co-solvent (MeOH):40.0; Total Flow: 100.0 g/min; Back Pressure: 100.0 bar; UV: 220 nm;Stack time: 4.5 min; Load/Inj: 13.0 mg; Solubility: MeOH; Total No ofinjections: 28; Instrument details: Make/Model: Thar SFC-200-005] toafford 140 mg (57% Yield) of(E)-3-(4-((1S,3S)-2-(3,3-difluorocyclobutyl)-3-methyl-2,3,4,9-tetrahydro-1H-pyrido[3,4-b]indol-1-yl)-3,5-difluorophenyl)acrylicacid as an off white solid. ¹H NMR (300 MHz, DMSO-d₆) δ 10.6 (s 1H),7.60-7.38 (m, 4H), 7.18 (d, J=7.5 Hz, 1H), 7.08-6.90 (m, 2H), 6.68 (d,J=15.9 Hz, 1H), 5.16 (s, 1H), 3.59-3.42 (m, 1H), 3.40-3.25 (m, 1H), 2.94(dd, J=14.9, 4.0 Hz, 2H), 2.90-2.71 (m, 1H), 2.71-2.56 (m, 1H),2.22-2.05 (m, 1H), 2.00-1.80 (m, 1H), 1.03 (d, J=6.6, 3H); MS (ESI) m/z459.26 [M+H]+; [α]_(D)=+32.0° (c 0.25, MeOH, 24° C.).

Compounds 9A and 9B are shown above and Table 1 with absolutestereochemistry arbitrarily assigned.

Example 10A(E)-3-(3,5-Difluoro-4-((1R,3R)-2-(4-methoxybenzyl)-3-methyl-2,3,4,9-tetrahydro-1H-pyrido[3,4-b]indol-1-yl)phenyl)acrylicacid (10A)

Step 1

To a stirred solution of (R)-1-(1H-indol-3-yl)propan-2-amine (1 g, 5.73mmol) in 3 mL of ethanol was added 4-methoxybenzaldehyde (0.781 g, 5.73mmol) and the mixture was stirred at 70° C. for 30 min. The resultingreaction mixture was cooled to 0° C., sodium borohydride (0.326 g, 8.59mmol) was added and the reaction was stirred for 1 h at rt. The reactionwas diluted with ethyl acetate (10 mL) and washed with saturated aqueousNH₄Cl solution (10 mL). The combined organic layers were dried oversodium sulfate, filtered and concentrated. The obtained residue waspurified by column chromatography (SiO₂, 2-3% MeOH/DCM) to afford 1.00 g(59% Yield) of (R)-1-(1H-indol-3-yl)-N-(4-methoxybenzyl)propan-2-amine.MS (ESI) m/z 295.18 [M+H]⁺.

Step 2

To a stirred solution of(R)-1-(1H-indol-3-yl)-N-(4-methoxybenzyl)propan-2-amine (300 mg, 1.09mmol) in toluene (5 mL) was added methyl(E)-3-(3,5-difluoro-4-formylphenyl)acrylate (230 mg, 1.09 mmol) andacetic acid (0.122 g, 2.03 mmol). The resulting mixture was stirred at90° C. for 5 h. The reaction mixture was diluted with EtOAc and washedwith water. The combined organic layers were dried over sodium sulfate,filtered and concentrated. The residue was purified by reverse phaseprep-HPLC to afford 230 mg (44% yield) of methyl(E)-3-(3,5-difluoro-4-((1R,3R)-2-(4-methoxybenzyl)-3-methyl-2,3,4,9-tetrahydro-1H-pyrido[3,4-b]indol-1-yl)phenyl)acrylateas a pale yellow solid. MS (ESI) m/z 503.21 [M+H]⁺.

Step 3

To a stirred solution of methyl(E)-3-(3,5-difluoro-4-((1R,3R)-2-(4-methoxybenzyl)-3-methyl-2,3,4,9-tetrahydro-1H-pyrido[3,4-b]indol-1-yl)phenyl)acrylate(80 mg, 0.150 mmol) in methanol (1.5 mL) was added an aqueous solutionof NaOH (0.212 mL, 1.59 mmol, 7.5M) at 0° C. and the mixture was stirredat rt for 5 h. The reaction mixture was concentrated under reducedpressure. The obtained residue was acidified with 1N HCl at 0° C.,diluted with EtOAc and washed with water. The combined organic layerswere dried over sodium sulfate, filtered and concentrated. The residuewas purified by reverse phase prep-HPLC to afford 25 mg (33% Yield) of(E)-3-(3,5-difluoro-4-((1R,3R)-2-(4-methoxybenzyl)-3-methyl-2,3,4,9-tetrahydro-1H-pyrido[3,4-b]indol-1-yl)phenyl)acrylicacid as an off white solid. ¹H NMR (300 MHz, DMSO-d₆) δ 12.8-12.4 (br s,1H), 10.6 (s, 1H), 7.44-7.37 (m, 3H), 7.21-7.14 (m, 4H), 7.02-6.90 (m,2H), 6.84-6.82 (m, 2H), 6.65-6.61 (m, 1H), 5.17 (s, 1H), 3.71 (s, 3H),3.68 (d, J=13.6 Hz, 1H), 3.45 (d, J=13.6 Hz, 1H), 2.86-2.84 (m, 1H),2.58-2.54 (m, 1H), 1.12 (m, 1H), 1.07-1.06 (d, J=6.4 Hz, 3H); MS (ESI)m/z 489.19 [M+H]⁺.

Examples 11A and 11B(E)-3-(4-((1R,3R)-2-(Bicyclo[1.1.1]pentan-1-yl)-3-methyl-2,3,4,9-tetrahydro-1H-pyrido[3,4-b]indol-1-yl)-3,5-difluorophenyl)acrylicacid (11A)

(E)-3-(4-((1S,3S)-2-(Bicyclo[1.1.1]pentan-1-yl)-3-methyl-2,3,4,9-tetrahydro-1H-pyrido[3,4-b]indol-1-yl)-3,5-difluorophenyl)acrylicacid (11B)

Step 1

To a solution of 1-(1H-indol-3-yl)propan-2-one (0.062 g, 0.51 mmol) inMeOH (1 mL) was added glacial acetic acid to adjust the pH to 5-6. Tothis solution was added bicyclo[1.1.1]pentan-1-amine as thehydrochloride salt (0.075 g, 0.43 mmol) followed by sodiumcyanoborohydride (0.054 g, 0.86 mmol). The reaction mixture was stirredat room temperature under a nitrogen atmosphere for 16 h. The solventwas removed under reduced pressure. Water (5 mL) was added and themixture was extracted with ethyl acetate (2×5 mL). The combined organiclayer was washed with saturated sodium bicarbonate solution, brine,dried over sodium sulfate, filtered and concentrated under reducedpressure. The crude residue was purified by flash column chromatography(SiO₂, 3-5% MeOH/DCM) to affordN-(1-(1H-indol-3-yl)propan-2-yl)bicyclo[1.1.1]pentan-1-amine (0.060 g,58%) as a light yellow solid. MS (ESI) m/z: 241.26 [M+H]⁺.

Step 2

To a solution ofN-(1-(1H-indol-3-yl)propan-2-yl)bicyclo[1.1.1]pentan-1-amine (1.3 g,5.41 mmol) in toluene (15 mL) were added methyl(E)-3-(3,5-difluoro-4-formylphenyl)acrylate (1.2 g, 4.87 mmol) andacetic acid (0.7 mL, 10.8 mmol). The resulting solution was stirred at80° C. for 2 h. The reaction mixture was cooled to room temperature andpoured into an aqueous solution of potassium carbonate (20 mL) andextracted with ethyl acetate (3×20 mL). The combined organic layers weredried over sodium sulfate, filtered and concentrated. The crude productwas purified by column chromatography (SiO₂, 40% EtOAc/hexanes) toprovide 1.0 g of a racemic mixture. The isomers were separated by chiralSFC [Chiral pak AD-H, (250×21 mm), 70 mL per min, liquid CO₂/IPA] toafford methyl(E)-3-(4-((1R,3R)-2-(bicyclo[1.1.1]pentan-1-yl)-3-methyl-2,3,4,9-tetrahydro-1H-pyrido[3,4-b]indol-1-yl)-3,5-difluorophenyl)acrylate(0.381 g, 17% yield) (Designated as Peak 1, retention time: 6.41 min)and methyl(E)-3-(4-((1S,3S)-2-(bicyclo[1.1.1]pentan-1-yl)-3-methyl-2,3,4,9-tetrahydro-1H-pyrido[3,4-b]indol-1-yl)-3,5-difluorophenyl)acrylate(0.481 g, 21% yield) (Designated as Peak 2, retention time: 9.59 min),both as yellow solids. The absolute stereochemistry for peak 1 and peak2 was arbitrarily assigned.

Methyl(E)-3-(4-((1R,3R)-2-(bicyclo[1.1.1]pentan-1-yl)-3-methyl-2,3,4,9-tetrahydro-1H-pyrido[3,4-b]indol-1-yl)-3,5-difluorophenyl)acrylate:MS (ESI) m/z: 449.6 [M+H]⁺.

Methyl(E)-3-(4-((1S,3S)-2-(bicyclo[1.1.1]pentan-1-yl)-3-methyl-2,3,4,9-tetrahydro-1H-pyrido[3,4-b]indol-1-yl)-3,5-difluorophenyl)acrylate:MS (ESI) m/z: 449.6 [M+H]⁺.

Step 3-a

To a solution of methyl(E)-3-(4-((1R,3R)-2-(bicyclo[1.1.1]pentan-1-yl)-3-methyl-2,3,4,9-tetrahydro-1H-pyrido[3,4-b]indol-1-yl)-3,5-difluorophenyl)acrylate(0.381 g, 0.850 mmol) in THF (4 mL) and MeOH (2 mL) was added an aqueoussodium hydroxide solution (1.2 mL, 9 mmol, 7.5M). The solution wasstirred at room temperature for 4 h. Water (10 mL) was added to thereaction mixture and the pH of the aqueous solution was adjusted to 5 byaddition of 2N HCl solution. The solution was extracted with diethylether (3×50 mL). The combined organic phase was dried over sodiumsulfate, filtered and concentrated under reduced pressure. The crudeproduct was purified by reverse phase HPLC [PURITAS PREP Cis (250×21.2mm), 17 mL/min, (3 mM ammonium acetate+0.02% Formic acid) inwater/acetonitrile, retention time 4.47 min] to afford(E)-3-(4-((1R,3R)-2-(bicyclo[1.1.1]pentan-1-yl)-3-methyl-2,3,4,9-tetrahydro-1H-pyrido[3,4-b]indol-1-yl)-3,5-difluorophenyl)acrylicacid (0.110 g, 29% yield) as a pale yellow solid. ¹H NMR (400 MHz,DMSO-d₆) δ 12.4 (s, 1H), 10.5 (s, 1H), 7.6 (d, J=16.0 Hz, 1H), 7.5 (d,J=10.0 Hz, 2H), 7.4 (d, J=8.0 Hz, 1H), 7.2 (d, J=7.6 Hz, 1H), 6.9 (m,2H), 6.7 (d, J=16.0 Hz, 1H), 5.3 (s, 1H), 3.6 (m, 1H), 2.9 (m, 1H), 2.6(m, 1H), 2.3 (s, 1H), 1.8 (d, J=8.4 Hz, 3H), 1.6 (d, J=1.2 Hz, 3H), 1.2(m, 3H); MS (ESI) m/z 435.4 [M+H]⁺.

Step 3-b

To a solution of methyl(E)-3-(4-((1S,3S)-2-(bicyclo[1.1.1]pentan-1-yl)-3-methyl-2,3,4,9-tetrahydro-1H-pyrido[3,4-b]indol-1-yl)-3,5-difluorophenyl)acrylate(0.481 g, 1.07 mmol) in THF (6 mL) and methanol (3 mL) was added anaqueous solution of sodium hydroxide solution (1.5 mL, 11.2 mmole,7.5M). The solution was stirred at room temperature for 4 h. The pH ofthe aqueous solution was adjusted to 5 by addition of 2N HCl solution.The solution was extracted with diethyl ether (3×70 mL). The combinedorganic phase was dried over sodium sulfate, filtered and concentratedunder reduced pressure. The residue was purified by reverse phase HPLC[PURITAS PREP Cis (250×21.2 mm), 17 mL/min, (3 mM ammonium acetate+0.02%formic acid) in water/acetonitrile, retention time: 5.29 min] to provide(E)-3-(4-((1S,3S)-2-(bicyclo[1.1.1]pentan-1-yl)-3-methyl-2,3,4,9-tetrahydro-1H-pyrido[3,4-b]indol-1-yl)-3,5-difluorophenyl)acrylicacid (0.153 g, 32% yield) as a pale yellow solid. ¹H NMR (400 MHz,DMSO-d₆) δ 12.4 (br s, 1H), 10.5 (s, 1H), 7.6 (d, J=16.0 Hz, 1H), 7.5(d, J=10.0 Hz, 2H), 7.4 (d, J=8.0 Hz, 1H), 7.2 (d, J=7.6 Hz, 1H), 6.9(m, 2H), 6.7 (d, J=16.0 Hz, 1H), 5.3 (s, 1H), 3.6 (m, 1H), 2.9 (m, 1H),2.6 (m, 1H), 2.3 (s, 1H), 1.8 (d, J=8.4 Hz, 3H), 1.6 (d, J=1.2 Hz, 3H),1.2 (m, 3H); MS (ESI) m/z: 435.6 [M+H]⁺.

The stereochemistry for compounds 11A and 11B shown above and in Table 1was arbitrarily assigned and later confirmed by independent synthesis.

Alternative Route to Synthesize Compound 11A (FIG. 2) Step 1

To a solution of benzaldehyde (PhCHO) (14.58 ml, 143 mmol) in EtOH (287ml) was added (R)-1-(1H-indol-3-yl)propan-2-amine 11-1 (25.0 g, 143mmol) and the reaction was heated to 50° C. for 3 h. The mixture wascooled to 0° C. and sodium borohydride (8.14 g, 214 mmol) was added inone portion and the reaction was stirred for 3 h at 0° C. The reactionwas poured into a saturated, aqueous sodium bicarbonate solution (200mL) and extracted with DCM (300 mL). The layers were separated and theaqueous layer was washed 3 times with DCM. The combined organic phasewas dried with sodium sulfate, filtered and concentrated under vacuum.The residue was purified on silica gel using an MPLC system (340 gcartridge) eluting from 60-100% EA/hexane to afford(R)—N-benzyl-1-(1H-indol-3-yl)propan-2-amine 11-2 (36 g, 95%). ¹H NMR(300 MHz, CDCl₃-d) δ 8.20-8.00 (s, 1H), 7.57 (d, J=7.9 Hz, 1H), 7.35 (d,J=8.0 Hz, 1H), 7.29-7.13 (m, 6H), 7.09 (t, J=7.4 Hz, 1H), 6.98 (s, 1H),3.89 (d, J=13.1 Hz, 1H), 3.74 (d, J=13.1 Hz, 1H), 3.22-3.01 (m, 1H),2.87 (t, J=7.5 Hz, 2H), 1.17 (d, J=6.2 Hz, 3H).

Step 2

1,1-Dibromo-2,2-bis(chloromethyl)cyclopropane (25 g, 84 mmol) wasdissolved in anhydrous n-Bu₂O (30 mL) at room temperature. The resultingsolution was cooled to −78° C. (dry ice/acetone cooling bath) and PhLi(100 ml, 168 mmol, 1.7M solution in n-Bu₂O) was added dropwise. Thereaction mixture was stirred at −78° C. for 5 minutes and then warmed to0° C. for 2 h. The white-yellow suspension oftricyclo[1.1.1.0^(1,3)]pentane 11-3 in n-Bu₂O was allowed to warm toroom temperature and stirred for a few minutes.

Step 3

(R)—N-benzyl-1-(1H-indol-3-yl)propan-2-amine 11-2 (27.8 g, 105 mmol) wasdissolved in anhydrous THF (90 mL) and treated with iPrMgCl—LiCl complex(162 mL, 211 mmol, 1.3M solution in THF) via syringe pump at roomtemperature. (Caution: vigorous gas evolution!) The resulting solutionwas vigorously stirred at room temperature for 30 min. The resultingmixture was added to the solution of tricyclo[1.1.1.0^(1,3)]pentane 11-3in n-Bu₂O that was prepared in step 2 at room temperature. The septumwas removed and the tube was sealed. The reaction mixture was vigorouslystirred at 60° C. for 16 hours. The heterogeneous solution was pouredinto a saturated aqueous solution of NH₄Cl (200 mL) at 0° C. The sealedtube was washed carefully with ethyl acetate and water. The mixture wastransferred to a separatory funnel and the layers were separated. Theaqueous layers were washed with ethyl acetate (2×250 mL). All of theorganic layers were combined, dried over sodium sulfate and concentratedunder vacuum. The crude residue was purified by a MPLC (340 g column)using hexane/ethyl acetate (10-90%) and(R)—N-(1-(1H-indol-3-yl)propan-2-yl)-N-benzylbicyclo[1.1.1]pentan-1-amine11-4 was obtained as a yellow oil (15.0 g, 45.4 mmol, 54% yield relativeto the quantity of 1,1-dibromo-2,2-bis(chloromethyl)cyclopropaneemployed). ¹H NMR (300 MHz, CDCl₃-d) δ 7.85-7.97 (br s, 1H), 7.53 (d,J=7.9 Hz, 1H), 7.36 (app t, J=7.5 Hz, 3H), 7.32-7.14 (m, 4H), 7.09 (t,J=7.5 Hz, 1H), 7.00 (d, J=2.0 Hz, 1H), 3.87 (d, J=15.1 Hz, 1H), 3.76 (d,J=15.1 Hz, 1H), 3.59-3.33 (m, 1H), 3.09 (dd, J=14.1, 4.8 Hz, 1H), 2.71(dd, J=14.1, 9.6 Hz, 1H), 2.30 (s, 1H), 1.92-1.70 (m, 6H), 1.06 (d,J=6.6 Hz, 3H).

Step 4

Palladium hydroxide [10% on charcoal (wet), 5.0 g] was added to asolution of(R)—N-(1-(1H-indol-3-yl)propan-2-yl)-N-benzylbicyclo[1.1.1]pentan-1-amine11-4 (15.5 g, 46.9 mmol) in EtOH (300 mL). The mixture was stirred undera hydrogen atmosphere (1 atm) at room temperature for 16 h. The solutionwas filtered through a pad of Celite® and the pad was washed with MeOHand CH₂Cl₂. The filtrate was concentrated under reduce pressure toobtain (R)—N-(1-(1H-indol-3-yl)propan-2-yl)bicyclo[1.1.1]pentan-1-amine11-5 (11.0 g, 98% yield). ¹H NMR (300 MHz, CDCl₃-d) δ 8.16-7.95 (br s,1H), 7.62 (d, J=7.9 Hz, 1H), 7.36 (d, J=8.0 Hz, 1H), 7.19 (t, J=7.4 Hz,1H), 7.12 (t, J=7.4 Hz, 1H), 7.02 (s, 1H), 3.25-3.11 (m, 1H), 2.88 (dd,J=14.2, 7.2 Hz, 1H), 2.74 (dd, J=14.2, 6.5 Hz, 1H), 2.36 (s, 1H),1.95-1.51 (m, 6H), 1.12 (d, J=6.2 Hz, 3H); MS (ESI) m/z 240.9 [M+H]⁺.

Step 5

To a stirred solution of(R)—N-(1-(1H-indol-3-yl)propan-2-yl)bicyclo[1.1.1]pentan-1-amine 11-5(800 mg, 3.2 mmol) in toluene (8 mL) was added(E)-methyl-3-(3,5-difluoro-4-formylphenyl) acrylate (750 mg, 3.2 mmol)followed by AcOH (0.36 mL, 6.4 mmol) and the mixture was heated at 90°C. for 5 h. The reaction mixture was cooled to rt, diluted with waterand extracted with ethyl acetate. The combined organic layer was driedover sodium sulfate, filtered and concentrated. The residue was purifiedby column chromatography (SiO₂, 20% ethyl acetate in hexanes) to affordmethyl(E)-3-(4-((1R,3R)-2-(bicyclo[1.1.1]pentan-1-yl)-3-methyl-2,3,4,9-tetrahydro-1H-pyrido[3,4-b]indol-1-yl)-3,5-difluorophenyl)acrylate(1.2 g, 2.7 mmol, 80% yield). Note: the product still contained about 4%cis isomer. A solution of methyl(E)-3-(4-((1R,3R)-2-(bicyclo[1.1.1]pentan-1-yl)-3-methyl-2,3,4,9-tetrahydro-1H-pyrido[3,4-b]indol-1-yl)-3,5-difluorophenyl)acrylate(1.2 g, 2.7 mmol) in toluene (8 mL) was kept in a pre-heated oil bath(80° C.) and stirred for 10 min at same temperature. Hexane (8 mL) wasadded slowly to the solution and the mixture was stirred at 80° C. for 1h. The reaction mixture was cooled to rt over a period of 1 h. Theresulting solids were filtered and dried under reduced pressure toafford methyl(E)-3-(4-((1R,3R)-2-(bicyclo[1.1.1]pentan-1-yl)-3-methyl-2,3,4,9-tetrahydro-1H-pyrido[3,4-b]indol-1-yl)-3,5-difluorophenyl)acrylate11-6 (700 mg, 60% overall yield). ¹H NMR (300 MHz, DMSO-d₆) δ 10.48 (brs, 1H), 7.63 (d, J=18.0 Hz, 1H), 7.50 (d, J=10.2 Hz, 2H), 7.38 (d, J=6.9Hz, 1H), 7.17 (d, J=7.2 Hz, 1H), 7.01-6.91 (m, 2H), 6.80 (d, J=16.2 Hz,1H), 5.33 (s, 1H), 3.73 (s, 3H), 3.61 (br s, 1H), 3.01-2.93 (m, 1H),2.57 (d, J=16.2 Hz, 1H), 2.24 (s, 1H), 1.77 (d, J=9.0 Hz, 3H), 1.57 (d,J=9.0 Hz, 3H), 1.08 (d, J=6 Hz, 3H); MS (ESI) m/z 449.10 [M+H]⁺.

Step 6

To a stirred solution of methyl(E)-3-(4-((1R,3R)-2-(bicyclo[1.1.1]pentan-1-yl)-3-methyl-2,3,4,9-tetrahydro-1H-pyrido[3,4-b]indol-1-yl)-3,5-difluorophenyl)acrylate11-6 (700 mg, 1.56 mmol) in a mixture of THF/H₂O (1:1, 10 mL) at 0° C.was added LiOH.H₂O (320 mg, 9.3 mmol). The resulting reaction mixturewas stirred at rt for 6 h. The mixture was concentrated under reducedpressure to remove solvent and the residue was diluted with water andwashed with diethyl ether. The aqueous layer was treated with aqueousHCl solution (1M) at 0° C. to adjust pH to ˜5. The precipitate thatformed was filtered, washed with water and dried under reduced pressureto afford(E)-3-(4-((1R,3R)-2-(bicyclo[1.1.1]pentan-1-yl)-3-methyl-2,3,4,9-tetrahydro-1H-pyrido[3,4-b]indol-1-yl)-3,5-difluorophenyl)acrylic acid 11A (0.500 g, 1.15 mmol, 74% yield). ¹H NMR (300 MHz,DMSO-d₆) δ 12.56 (br s, 1H), 10.58 (br s, 1H), 7.55 (d, J=15.9 Hz, 1H),7.45 (d, J=10.2 Hz, 2H), 7.39 (d, J=7.5 Hz, 1H), 7.17 (d, J=7.2 Hz, 1H),6.99 (dd, J=7.5, 6.0 Hz, 1H), 6.93 (dd, J=9.0, 6.3 Hz, 1H), 6.67 (d,J=15.9 Hz, 1H), 5.33 (s, 1H), 3.68-3.58 (m, 1H), 2.96 (dd, J=15.3, 4.2Hz, 1H), 2.57 (dd, J=15.0, 1.5 Hz, 1H), 2.24 (s, 1H), 1.78 (d, J=9.3 Hz,3H), 1.58 (d, J=9.6 Hz, 3H). 1.08 (d, J=6.6 Hz, 3H); MS (ESI) m/z 435.13[M+H]+; [α]²⁵ _(D) −46.00 (c 0.5, MeOH); mp: 171-173° C.

Example 11C(E)-3-(4-((1S,3R)-2-(Bicyclo[1.1.1]pentan-1-yl)-3-methyl-2,3,4,9-tetrahydro-1H-pyrido[3,4-b]indol-1-yl)-3,5-difluorophenyl)acrylicacid (11C)

Step 1

To a stirred solution of(R)—N-(1-(1H-indol-3-yl)propan-2-yl)bicyclo[1.1.1]pentan-1-amine (7.3 g,30.4 mmol) in toluene (150 mL) was added methyl(E)-3-(3,5-difluoro-4-formylphenyl)acrylate (6.87 g, 30.4 mmol) followedby AcOH (3.5 mL, 60.8 mmol) and the resulting reaction mixture wasstirred at 90° C. for 4 h. The reaction mixture was cooled to roomtemperature, diluted with water and extracted with ethyl acetate. Thecombined organic layers were dried over Na₂SO₄, filtered andconcentrated. The residue was purified by column chromatography (SiO₂,20% ethyl acetate/hexanes) to afford a solid which was triturated withn-pentane (100 mL). The resulting solids were filtered. The motherliquor (containing the pentane washings) was concentrated and purifiedby reversed phase HPLC [Mobile phase: (A) 10 mM aqueous ammoniumbicarbonate, (B) Acetonitrile; Flow: 19 mL/min; Column: X Select C18(150×19 mm) 5 μm; Gradient-(Time (min)/% B): 0.1/75, 10/80, 12/80,12.1/98, 14/98, 14.1/75, 17/75, Solubility: ACN+H₂O+THF] to affordmethyl(E)-3-(4-((1S,3R)-2-(bicyclo[1.1.1]pentan-1-yl)-3-methyl-2,3,4,9-tetrahydro-1H-pyrido[3,4-b]indol-1-yl)-3,5-difluorophenyl)acrylate(100 mg, 0.22 mmol, 0.73% yield) as an off-white solid. MS (ESI) r/z449.34 [M+H]⁺.

Step 2

To a stirred solution of methyl(E)-3-(4-((1S,3R)-2-(bicyclo[1.1.1]pentan-1-yl)-3-methyl-2,3,4,9-tetrahydro-1H-pyrido[3,4-b]indol-1-yl)-3,5-difluorophenyl)acrylate(100 mg, 0.22 mmol) in a mixture of THF and water (1:1, total of 2 mL)at 0° C. was added LiOH.H₂O (46 mg, 1.33 mmol). The resulting reactionmixture was stirred at rt for 4 h and then concentrated. Water (10 mL)was added to the residue and the mixture was cooled to 0° C. and treatedwith 0.1 M HCl to adjust pH to ˜6. The reaction mixture was extractedwith Et₂O (2×20 mL). The organic layer was washed with water (2×20 mL),dried over Na₂SO₄, filtered and concentrated to afford(E)-3-(4-((1S,3R)-2-(bicyclo[1.1.1]pentan-1-yl)-3-methyl-2,3,4,9-tetrahydro-1H-pyrido[3,4-b]indol-1-yl)-3,5-difluorophenyl)acrylicacid (30 mg, 0.06 mmol, 31% yield) as a pale yellow solid. ¹H NMR (400MHz, DMSO) δ 12.57 (br s, 1H), 10.75 (s, 1H), 7.49 (d, J=16.0 Hz, 1H),7.40 (d, J=9.6 Hz, 3H), 7.24 (d, J=8.0 Hz, 1H), 7.02 (t, J=6.8 Hz, 1H),6.95 (t, J=6.8 Hz, 1H), 6.63 (d, J=16.0 Hz, 1H), 5.40 (s, 1H), 3.52-3.48(m, 1H), 2.92 (dd, J=15.6, 5.6 Hz, 1H), 2.53 (s, 1H), 2.32 (s, 1H), 1.80(s, 6H), 1.02 (d, J=7.2 Hz, 3H); MS (ESI) m/z 435.25.

Example 11D(E)-3-(4-((1R,3R)-2-(Bicyclo[1.1.1]pentan-1-yl)-3-methyl-2,3,4,9-tetrahydro-1H-pyrido[3,4-b]indol-1-yl-1-d)-3,5-difluorophenyl)acrylicacid (11D)

Step 1

To a stirred solution of(R)—N-(1-(1H-indol-3-yl)propan-2-yl)bicyclo[1.1.1]pentan-1-amine (0.100g, 0.416 mmol) in toluene (1.0 mL) was added methyl(E)-3-(3,5-difluoro-4-(formyl-d)phenyl)acrylate (0.095 g, 0.416 mmol)and acetic acid (0.050 g, 0.832 mmol) and the mixture was heated at 90°C. for 5 h. The reaction mixture was cooled to rt, diluted with EtOAc(10 mL) and washed with aqueous saturated solution of sodiumbicarbonate. The combined organic layers were dried over Na₂SO₄,filtered and concentrated. The residue was purified by flashchromatography (SiO₂, 20% ethyl acetate/hexane) to afford methyl(E)-3-(4-((1R,3R)-2-(bicyclo[1.1.1]pentan-1-yl)-3-methyl-2,3,4,9-tetrahydro-1H-pyrido[3,4-b]indol-1-yl-1-d)-3,5-difluorophenyl)acrylate(0.122 mg, 0.271 mmol, 65% yield) as a white solid. The resultantmaterial was dissolved in toluene (1 mL) which was pre-heated to 90° C.Hexane, pre-heated to 70° C., was slowly added. The mixture was cooledto rt and then stored at 4° C. for 12 h. The resulting solid wasfiltered to afford methyl(E)-3-(4-((1R,3R)-2-(bicyclo[1.1.1]pentan-1-yl)-3-methyl-2,3,4,9-tetrahydro-1H-pyrido[3,4-b]indol-1-yl-1-d)-3,5-difluorophenyl)acrylate(0.029 mg, 0.065 mmol, 16% yield); MS (APCI) m/z 450.20 [M+H]⁺.

Step 2

To a stirred solution of methyl(E)-3-(4-((1R,3R)-2-(bicyclo[1.1.1]pentan-1-yl)-3-methyl-2,3,4,9-tetrahydro-1H-pyrido[3,4-b]indol-1-yl-1-d)-3,5-difluorophenyl)acrylate(0.029 mg, 0.065 mmol) in THF/water (1:1, total of 0.8 mL) at 0° C. wasadded LiOH (0.017 g, 0.400 mmol) and the reaction was stirred at rt for5 h. The organic volatiles were removed under reduced pressure at 20° C.The residue was treated with an aqueous solution of hydrogen chloride(1N) at 0° C. to adjust pH to 6. The aqueous layer was extracted withdiethyl ether (2×10 mL) and the combined organic layer was washed withwater, dried over sodium sulfate, filtered and concentrated. The residuewas triturated with diethyl ether: pentane (1:10, 3 mL total) which wereremoved under reduced pressure to afford(E)-3-(4-((1R,3R)-2-(bicyclo[1.1.1]pentan-1-yl)-3-methyl-2,3,4,9-tetrahydro-1H-pyrido[3,4-b]indol-1-yl-1-d)-3,5-difluorophenyl)acrylicacid as a white solid (0.024 mg, 0.055 mmol, 83% yield). ¹H NMR (400MHz, DMSO-d₆) δ 12.6 (br s, 1H), 10.6 (br s, 1H), 7.54 (d, J=15.8 Hz,1H), 7.45 (d, J=10.2 Hz, 2H), 7.39 (d, J=7.9 Hz, 1H), 7.18 (d, J=7.9 Hz,1H), 7.02-6.97 (m, 1H), 6.97-6.92 (m, 1H), 6.67 (d, J=16.1 Hz, 1H),3.68-3.58 (m, 1H), 2.96 (dd, J=14.9, 5.0 Hz, 1H), 2.62-2.54 (m, 1H),2.25 (s, 1H), 1.77 (d, J=9.0 Hz, 3H), 1.59 (d, J=9.2 Hz, 3H), 1.08 (d,J=6.5 Hz, 3H); MS (APCI) m/z 436.2 [M+H]⁺.

Example 12A Ethyl(E)-3-(4-((1R,3R)-2-(Bicyclo[1.1.1]pentan-1-yl)-3-methyl-2,3,4,9-tetrahydro-1H-pyrido[3,4-b]indol-1-yl)-3,5-difluorophenyl)acrylate(12A)

Step 1

4-Bromo-2,6-difluorobenzaldehyde (7.0 g, 31.7 mmol) and ethyl acrylate(4.7 g, 47.5 mmol) were combined in a sealed tube and the solution wasdegassed thoroughly with argon for 10 min. N,N-dimethylacetmide (70 mL),tri-o-tolylphosphine (0.92 g, 1.36 mmol), palladium(II) acetate (0.34 g,0.678 mmol) and triethylamine (9 mL, 27.1 mmol) were added and themixture was degassed again for 15 min. The resulting reaction mixturewas stirred at 80° C. for 6 h. The reaction mixture was cooled to roomtemperature, filtered through a Celite pad which was washed thoroughlywith methanol (20 mL). The obtained filtrate was concentrated underreduced pressure. The crude compound was purified by flashchromatography (SiO₂, 1:9 ethyl acetate/hexane) to afford ethyl(E)-3-(3,5-difluoro-4-formylphenyl)acrylate (4.5 g, 18.7 mmol, 59%yield) as a pale yellow solid.

Step 2

To a stirred solution of(R)—N-(1-(1H-indol-3-yl)propan-2-yl)bicyclo[1.1.1]pentan-1-amine (500mg, 2.34 mmol) in toluene (5.8 mL) was added ethyl(E)-3-(3,5-difluoro-4-formylphenyl)acrylate (500 mg, 2.57 mmol) andacetic acid (280 mg, 4.67 mmol) and the mixture was heated at 90° C. for5 h. The reaction mixture was diluted with EtOAc and washed with water.The combined organic layers were dried over Na₂SO₄, filtered andconcentrated. The residue was purified by flash chromatography (SiO₂,20% ethyl acetate/hexanes) to afford ethyl(E)-3-(4-((1R,3R)-2-(bicyclo[1.1.1]pentan-1-yl)-3-methyl-2,3,4,9-tetrahydro-1H-pyrido[3,4-b]indol-1-yl)-3,5-difluorophenyl)acrylate(700 mg, 1.51 mmol, 65% yield) as a pale yellow solid. ¹H NMR (400 MHz,DMSO-d₆) δ 10.50 (s, 1H), 7.60 (d, J=16.0 Hz, 1H), 7.48 (d, J=10.0 Hz,2H), 7.38 (d, J=7.2 Hz, 1H), 7.17 (d, J=8.0 Hz, 1H), 7.00-6.92 (m, 2H),6.77 (d, J=16.4 Hz, 1H), 5.33 (s, 1H), 4.19 (q, J=7.6 Hz, 2H), 3.63-3.61(m, 1H), 2.95 (dd, J=14.8 Hz, 4.0 Hz, 1H), 2.57 (dd, J=14.8 Hz, 2.0 Hz,1H), 2.24 (s, 1H), 1.77 (d, J=8.4 Hz, 3H), 1.58 (d, J=8.0 Hz, 3H), 1.25(t, J=7.2 Hz, 3H), 1.08 (d, J=6.4 Hz, 3H); ¹⁹F NMR (400 MHz, DMSO-d₆) δ−112.01; MS (ESI) m/z 463.36 [M+H]⁺.

Examples 13A and 13B(E)-3-(3,5-Difluoro-4-((1S,3S)-2-(2-fluoro-2-methylpropyl)-6-hydroxy-3-methyl-2,3,4,9-tetrahydro-1H-pyrido[3,4-b]indol-1-yl)phenyl)acrylicacid (13A)

(E)-3-(3,5-Difluoro-4-((1R,3R)-2-(2-fluoro-2-methylpropyl)-6-hydroxy-3-methyl-2,3,4,9-tetrahydro-1H-pyrido[3,4-b]indol-1-yl)phenyl)acrylicacid (13B)

Step 1

Ammonium acetate (1.18 g, 15.3 mmol) was added in one portion to themixture of 5-(benzyloxy)-1H-indole-3-carbaldehyde (3.5 g, 13.93 mmol)and nitroethane (14.9 ml, 209 mmol) and heated at reflux for 8 hours.The reaction mixture was cooled to room temperature and excessnitroethane was removed in vacuo. Saturated aqueous NaHCO₃ solution (15mL) was added and the resulting mixture was extracted with ethyl acetate(3×20 mL). The organic layers were combined, dried over anhydrousNa₂SO₄, filtered and concentrated in vacuo. The crude product waspurified by column chromatography (SiO₂, 0-50% EtOAc in hexane) toafford (Z)-5-(benzyloxy)-3-(2-nitroprop-1-en-1-yl)-1H-indole (1.7 g, 40%yield) as a yellow solid. MS (APCI) m/z 309.12 [M+H]⁺.

Step 2

To a stirred solution of(Z)-5-(benzyloxy)-3-(2-nitroprop-1-en-1-yl)-1H-indole (1 g, 3.24 mmol)was added LAH (4.86 mL, 9.73 mmol, 2M in THF) dropwise at 0° C. andheated at reflux for 18 hours. The reaction mixture was cooled to rt andquenched with cold water slowly (0.4 mL), 15% aqueous NaOH solution(0.80 mL) and water (1.2 mL). The resulting solid was extracted withEtOAc (3×10 mL). The combined organic layer was dried over sodiumsulfate, filtered, and concentrated. The resulting residue was purifiedby column chromatography (SiO₂, 0-20% methanol in dichloromethane) toafford 1-(5-(benzyloxy)-1H-indol-3-yl)propan-2-amine (0.46 g, 51%yield). MS (APCI) m/z 281.16 [M+H]⁺.

Step 3

To a stirred solution of 1-(5-(benzyloxy)-1H-indol-3-yl)propan-2-amine(0.30 g, 1.070 mmol) in 1,4-dioxane (3.6 mL) was added2-fluoro-2-methylpropyl trifluoromethanesulfonate (0.300 g, 1.34 mmol)and N,N-diisopropylethylamine (0.373 ml, 2.14 mmol) and the reaction washeated at 90° C. for 3 h. The reaction mixture was cooled to roomtemperature and diluted with water (20 mL). The mixture was extractedwith EtOAc (2×15 mL). The combined organic layer was dried over sodiumsulfate, filtered and concentrated. The residue was purified by columnchromatography (60-80% EtOAc in hexane) to affordN-(1-(5-(benzyloxy)-1H-indol-3-yl)propan-2-yl)-2-fluoro-2-methylpropan-1-amine(0.22 g, 58% yield) MS (APCI) m/z 355.21 [M+H]⁺.

Step 4

To a stirred solution ofN-(1-(5-(benzyloxy)-1H-indol-3-yl)propan-2-yl)-2-fluoro-2-methylpropan-1-amine(0.27 g, 0.762 mmol) in MeOH (3.81 ml) was added palladium hydroxide (20wt/wt %) (0.047 g, 0.076 mmol) The reaction was stirred under 1 atm ofhydrogen gas for 4 h. The reaction mixture was filtered through a Celitepad and the filtrate was concentrated under reduced pressure to afford3-(2-((2-fluoro-2-methylpropyl)amino)propyl)-1H-indol-5-ol (0.16 g, 79%yield) MS (APCI) m/z 265.16 [M+H]⁺.

Step 5

To a stirred solution of3-(2-((2-fluoro-2-methylpropyl)amino)propyl)-1H-indol-5-ol (0.15 g,0.567 mmol) in toluene (2.8 mL) were added ethyl(E)-3-(3,5-difluoro-4-formylphenyl)acrylate (0.150 g, 0.624 mmol) andacetic acid (0.07 g, 1.14 mmol) and the mixture was heated at 80° C. for4 h. The reaction mixture was diluted with EtOAc and washed with water.The organic layer was separated and the aqueous layer was extracted withethyl acetate (2×15 mL). The combined organic layer was dried oversodium sulfate, filtered and concentrated. The residue was purified bycolumn chromatography (SiO₂, 15-60% EtOAc in hexane) to afford ethyl(E)-3-(3,5-difluoro-4-((1R,3R)-2-(2-fluoro-2-methylpropyl)-6-hydroxy-3-methyl-2,3,4,9-tetrahydro-1H-pyrido[3,4-b]indol-1-yl)phenyl)acrylate(0.16 g, 0.329 mmol, 58% yield, pale yellow solid) as a mixture ofenantiomers MS (APCI) m/z 487.21 [M+H]⁺.

Step 6

To a stirred solution of racemic ethyl(E)-3-(3,5-difluoro-4-((1R,3R)-2-(2-fluoro-2-methylpropyl)-6-hydroxy-3-methyl-2,3,4,9-tetrahydro-1H-pyrido[3,4-b]indol-1-yl)phenyl)acrylate(0.16 g, 0.329 mmol) in a mixture of MeOH:THF:water (1:1:1, total of 3mL) at 0° C. was added sodium hydroxide (0.04 g, 0.987 mmol). Thereaction was stirred at rt for 2 h. After the reaction was completed,the mixture was concentrated under reduced pressure. The residue wasacidified with an aqueous solution of citric acid (1M) at 0° C. Ethylacetate was added to dissolve the precipitate. The organic layer wasseparated, dried over sodium sulfate, filtered and concentrated toobtain a mixture of enantiomers:(E)-3-(3,5-difluoro-4-((1R,3R)-2-(2-fluoro-2-methylpropyl)-6-hydroxy-3-methyl-2,3,4,9-tetrahydro-1H-pyrido[3,4-b]indol-1-yl)phenyl)acrylicacid (0.11 g, 73.0% yield) as a pale yellow solid. MS (APCI) m/z 459.18[M+H]⁺.

Step 7

120 mg of racemic(E)-3-(3,5-difluoro-4-((1R,3R)-2-(2-fluoro-2-methylpropyl)-6-hydroxy-3-methyl-2,3,4,9-tetrahydro-1H-pyrido[3,4-b]indol-1-yl)phenyl)acrylicacid was purified by SFC (Preparative SFC Conditions: Column/dimensionsChiralcel OD-H (250×30 mm), 5 μm; % CO₂: 5.0; % Co-solvent (MeOH): 35.0;Total Flow: 100.0 g/min; Back Pressure: 100.0 bar; UV: 210 nm; Stacktime: 5.5 min; Load/Inj: 6.5 mg) to afford(E)-3-(3,5-Difluoro-4-((1R,3R)-2-(2-fluoro-2-methylpropyl)-6-hydroxy-3-methyl-2,3,4,9-tetrahydro-1H-pyrido[3,4-b]indol-1-yl)phenyl)acrylicacid (Designated as Peak 1) (22 mg, 0.04 mmol, 18% yield). ¹H NMR (300MHz, DMSO-d₆) δ 10.2 (s, 1H), 8.53 (br s, 1H), 7.45 (d, J=16.8 Hz, 1H),7.40 (d, J=10.5 Hz, 2H), 6.96 (d, J=8.4 Hz, 1H), 6.71 (d, J=2.1, 1H),6.64 (d, J=16.2 Hz, 1H), 6.51 (dd, J=9.0 Hz, 2.7 Hz, 1H), 5.16 (s, 1H),3.53-3.45 (m, 1H), 2.91-2.73 (m, 2H), 2.44-2.26 (m, 2H), 1.19 (d, J=21.3Hz, 3H), 1.12 (d, J=21.6 Hz, 3H), 1.04 (d, J=6.6 Hz, 3H), carboxylicacid proton not observed; MS (ESI) m/z 459.32 [M+H]⁺.(E)-3-(3,5-Difluoro-4-((1S,3S)-2-(2-fluoro-2-methylpropyl)-6-hydroxy-3-methyl-2,3,4,9-tetrahydro-1H-pyrido[3,4-b]indol-1-yl)phenyl)acrylicacid (Designated as Peak 2) (20 mg 0.04 mmol, 18% yield) as an off whitesolid. ¹H NMR (300 MHz, DMSO-d₆) δ 10.2 (s, 1H), 8.53 (br s, 1H), 7.34(d, J=16.2 Hz, 1H), 7.32 (d, J=10.6 Hz, 2H), 6.96 (d, J=8.4 Hz, 1H),6.71 (d, J=2.1, 1H), 6.59 (d, J=16.2 Hz, 1H), 6.50 (dd, J=8.7, 2.1 Hz,1H), 5.15 (s, 1H), 3.51-3.42 (m, 1H), 2.91-2.73 (m, 2H), 2.44-2.27 (m,2H), 1.19 (d, J=21.3 Hz, 3H), 1.12 (d, J=21.0 Hz, 3H), 1.04 (d, J=6.6Hz, 3H), carboxylic acid proton not observed; MS (ESI) m/z 459.29[M+H]⁺.

Compounds 13A and 13B are shown above and in Table 1 with absolutestereochemistry arbitrarily assigned.

Example 14A(E)-3-(3,5-Difluoro-4-((1R,3R)-2-((3-fluorobicyclo[1.1.1]pentan-1-yl)methyl)-3-methyl-2,3,4,9-tetrahydro-1H-pyrido[3,4-b]indol-1-yl)phenyl)acrylicacid (14A)

Step 1

To a stirred suspension of 3-fluorobicyclo[1.1.1]pentane-1-carboxylicacid (560 mg, 4.3 mmol), in anhydrous THF (5 mL) was added a solution ofpropylphosphonic anhydride (5.5 mL, 8.6 mmol, 50 wt % in EtOAc) andN,N-diisopropylethylamine (1.8 mL, 8.6 mmol) at 0° C., and the mixturewas stirred for 20 min at the same temperature.(R)-1-(1H-indol-3-yl)propan-2-amine (500 mg, 2.8 mmol) was added intothe reaction mixture at 0° C. and the mixture was stirred at rt for 18h. After completion of the reaction as indicated by TLC, the reactionmixture was diluted with ice cold water and extracted with ethyl acetate(2×50 mL). The combined organic layers were dried over sodium sulfate,filtered and concentrated. The resultant residue was purified by flashchromatography (SiO₂, 25% ethyl acetate/hexanes) to afford(R)—N-(1-(1H-indol-3-yl)propan-2-yl)-3-fluorobicyclo[1.1.1]pentane-1-carboxamide(500 mg, 1.75 mmol, 60% yield) as a pale brown liquid. MS (ESI) m/z287.25 [M+H]⁺.

Step 2

To a stirred suspension of(R)—N-(1-(1H-indol-3-yl)propan-2-yl)-3-fluorobicyclo[1.1.1]pentane-1-carboxamide(500 mg, 1.7 mmol), in dry THF (5 mL) was added a solution of borane THFcomplex (3.5 mL, 3.5 mmol, 1.0M in THF) at 0° C. and the mixture wasstirred at rt for 16 h. The completion of the reaction (as monitored byTLC) was determined by consumption of starting material. The reactionmixture was cooled to rt followed by addition of methanol (10 mL) andthen the mixture was stirred at room temperature for 1 h. The reactionmixture was diluted with water and extracted with ethyl acetate (2×50mL). The combined organic layer was dried over sodium sulfate, filteredand concentrated. The resultant residue was purified by flashchromatography (SiO₂, 80% ethyl acetate/hexanes) to afford(R)—N-((3-fluorobicyclo[1.1.1]pentan-1-yl)methyl)-1-(1H-indol-3-yl)propan-2-amine(450 mg, 1.65 mmol, 94% yield) as an off white solid. MS (ESI) m/z273.53 [M+H]⁺.

Step 3

To a stirred solution of(R)—N-((3-fluorobicyclo[1.1.1]pentan-1-yl)methyl)-1-(1H-indol-3-yl)propan-2-amine(350 mg, 1.2 mmol) in toluene (3 mL) was added methyl(E)-3-(3,5-difluoro-4-formylphenyl)acrylate (290 mg, 1.2 mmol), followedby acetic acid (154 mg, 2.5 mmol) at room temperature. The resultingmixture was stirred at 90° C. for 6 h and cooled to room temperature.The reaction mixture was diluted with water and extracted with ethylacetate (2×50 mL). The combined organic layers were dried over Na₂SO₄,filtered and concentrated under reduced pressure to afford crudecompound (E)-methyl3-(3,5-difluoro-4-((1R,3R)-2-((3-fluorobicyclo[1.1.1]pentan-1-yl)methyl)-3-methyl-2,3,4,9-tetrahydro-1H-pyrido[3,4-b]indol-1-yl)phenyl)acrylate(480 mg, 0.99 mmol, 77% yield) as a brown liquid which was used in thenext step without purification. MS (ESI) m/z 481.86 [M+H]⁺.

Step 4

To a stirred solution of (E)-methyl3-(3,5-difluoro-4-((1R,3R)-2-((3-fluorobicyclo[1.1.1]pentan-1-yl)methyl)-3-methyl-2,3,4,9-tetrahydro-1H-pyrido[3,4-b]indol-1-yl)phenyl)acrylate(600 mg, 1.25 mmol) in a mixture of THF/methanol/water (1:1:1, total of6 mL) at 0° C. was added NaOH (100 mg, 2.49 mmol). The mixture wasstirred at rt for 5 h. The volatiles were removed under reducedpressure. The resulting residue was acidified with aqueous hydrogenchloride solution (1M) at 0° C. to adjust pH to 5, and the aqueous phasewas extracted with EtOAc (3×50 mL). The combined organic layer was driedover Na₂SO₄, filtered and concentrated. The crude product was furtherpurified by SFC [Column/dimensions: Chiralcel OD-H (250×30 mm), 5 amsilica; % CO₂: 70.0%; % Co-solvent (MeOH): 30.0%; Total Flow: 100.0g/min; Back Pressure: 100.0 bar; UV: 212 nm; Stack time: 5.80 min;Load/Inj 5.2 mg; Solubility: Methanol; Total No of injections: 130;Instrument details (Make/Model): Thar SFC-200-005]; to afford(E)-3-(3,5-difluoro-4-((1R,3R)-2-((3-fluorobicyclo[1.1.1]pentan-1-yl)methyl)-3-methyl-2,3,4,9-tetrahydro-1H-pyrido[3,4-b]indol-1-yl)phenyl)acrylicacid (220 mg, 0.47 mmol, 37% yield) as an off white solid. Traces of anunknown aliphatic impurity that were observed by ¹H NMR. Furtherpurification by reverse phase HPLC [Mobile phase: (A) 10 mM aqueousammonium bicarbonate, (B) acetonitrile; Flow: 19 mL/min; column: XBRIDGEC18 (150×19 mm) 5 am Gradient-(Time (min)/% B): 0.1/30, 10/60, 11/60,11.1/99, 13/99, 13.1/10, 15/10] to give pure(E)-3-(3,5-difluoro-4-((1R,3R)-2-((3-fluorobicyclo[1.1.1]pentan-1-yl)methyl)-3-methyl-2,3,4,9-tetrahydro-1H-pyrido[3,4-b]indol-1-yl)phenyl)acrylicacid (50 mg, 0.17 mmol, 8.6% yield). ¹H NMR (400 MHz, DMSO-d₆) δ 10.6(s, 1H), 7.48 (d, J=15.6 Hz, 1H), 7.43 (d, J=11.1 Hz, 2H), 7.40 (d,J=7.5 Hz, 1H), 7.18 (d, J=7.2 Hz, 1H), 7.02-6.92 (m, 2H), 6.68 (d,J=14.7 Hz, 1H), 5.13 (s, 1H), 3.37-3.32 (m, 1H), 2.95 (d, J=15 Hz, 2H),2.59 (d, J=13.2 Hz, 2H), 1.82 (d, J=7.8 Hz, 3H), 1.70 (d, J=7.8 Hz, 3H),1.03 (d, J=6.3 Hz, 3H), proton of carboxylic acid not observed; MS (ESI)m/z 467.38 [M+H]+; [α]²⁵ _(D) −90.00 (c 0.5, MeOH).

Example 15A(E)-3-(3,5-Difluoro-4-((1R,3R)-2-(2-fluoro-2-methylpropyl)-7-hydroxy-3-methyl-2,3,4,9-tetrahydro-1H-pyrido[3,4-b]indol-1-yl)phenyl)acrylicacid (15A)

Step 1

To a suspension of(R)-2-(((9H-fluoren-9-yl)methoxy)carbonylamino)propanoic acid (10 g,32.1 mmol) in DCM (100 mL) at 0° C. was added oxalyl chloride (4.3 mL,48.2 mmol), followed by a catalytic amount of DMF (0.18 mL, 10 mol %).The mixture was stirred at room temperature for 4 h and thenconcentrated. The resulting residue was dissolved in toluene andconcentrated repeatedly (2×50 mL) to afford crude compound(9H-fluoren-9-yl)methyl (R)-(1-chloro-1-oxopropan-2-yl)carbamate (22 g,crude weight) as a pale yellow solid.

Step 2

Ethylmagnesium bromide (44 mL, 134.5 mmol, 3.0M solution in Et₂O) wasadded dropwise at 0° C. to a solution of 6-(benzyloxy)-1H-indole (10 g,44.8 mmol) over a period of 1 h in DCM (100 mL) under an atmosphere ofargon. The resultant reaction mixture was warmed to room temperature andstirred for an additional 1 h. The above reaction mixture was cooled to0° C. and treated with a solution of (9H-fluoren-9-yl)methyl(R)-(1-chloro-1-oxopropan-2-yl)carbamate (22 g, 67.2 mmol, crude) in DCM(100 mL) under an atmosphere of argon. After the addition was complete,the reaction was warmed to room temperature and stirred at rt for 12 h.The reaction mixture was cooled back to 0° C. and the excess ofunreacted Grignard reagent was destroyed with aqueous HCl (200 mL, 2N).The organic layer was separated and the aqueous layer was extracted withCH₂Cl₂ (2×200 mL). The combined organic layer was washed with waterfollowed by brine, dried over sodium sulfate, filtered and concentratedto afford (R)-(9H-Fluoren-9-yl)methyl1-(6-(benzyloxy)-1H-indol-3-yl)-1-oxopropan-2-ylcarbamate (22.0 g, 42.6mmol, crude) as a brown liquid. MS (ESI) m/z 517.35 [M+H]⁺.

Step 3

To a solution of (R)-(9H-Fluoren-9-yl)methyl1-(6-(benzyloxy)-1H-indol-3-yl)-1-oxopropan-2-ylcarbamate (20 g, 38.75mmol, crude) in a mixture of acetonitrile/IPA (7:1, total of 200 mL) wasadded sodium borohydride (14.3 g, 388 mmol) in several portions underargon atmosphere at 0° C. The mixture was heated to reflux for 15 h.After completion of the reaction based on complete consumption ofstarting material (as monitored by TLC), the reaction mixture was cooledback to 0° C. Methanol (50 mL) was added to destroy excess reagent andthe resulting mixture was stirred at rt for 30 min. Water (500 mL) wasadded and the aqueous phase was extracted with ethyl acetate (3×200 mL).The combined organic layer was washed with water, brine, dried oversodium sulfate, filtered and concentrated under reduced pressure. Theresidue was triturated with pentane to afford crude compound,(R)-1-(6-(benzyloxy)-1H-indol-3-yl)propan-2-amine (9 g, 25.4 mmol), asan off white solid used as is in the subsequent reaction. MS (ESI) m/z281.47 [M+H]⁺.

Step 4

To a stirred solution of(R)-1-(6-(benzyloxy)-1H-indol-3-yl)propan-2-amine (9 g, 32.1 mmol,crude) in 1,4-dioxane (80 mL) was added 2-fluoro-2-methylpropyltrifluoromethanesulfonate (7.9 g, 35.4 mmol) andN,N-diisopropylethylamine (8.8 mL, 48.21 mmol). The reaction was heatedto 90° C. for 3 h, cooled to room temperature and diluted with water (50mL). The aqueous layer was extracted with EtOAc (2×50 mL). The combinedorganic phase was dried over sodium sulfate, filtered and concentrated.The resultant residue was purified by flash chromatography (SiO₂, 50%ethyl acetate in petroleum ethers) to afford(R)—N-(1-(6-(benzyloxy)-1H-indol-3-yl)propan-2-yl)-2-fluoro-2-methylpropan-1-amine(4 g, 11.3 mmol, 26% yield over 3 steps). MS (ESI) m/z 355.37 [M+H]⁺.

Step 5

To a stirred solution of(R)—N-(1-(6-(benzyloxy)-1H-indol-3-yl)propan-2-yl)-2-fluoro-2-methylpropan-1-amine(4 g, 11.3 mmol) in EtOAc (50 mL) was added 10% wet Pd/C (800 mg). Thereaction was stirred at rt for 12 h under 1 atm of hydrogen gas. Themixture was filtered through a Celite pad. The filtrate was concentratedunder reduced pressure to afford(R)-3-(2-(2-fluoro-2-methylpropylamino)propyl)-1H-indol-6-ol (1.8 g,6.81 mmol, 64% yield). MS (ESI) m/z 265.17 [M+H]⁺.

Step 6

To a stirred solution of(R)-3-(2-(2-fluoro-2-methylpropylamino)propyl)-1H-indol-6-ol (1.8 g,6.81 mmol) in toluene (30 mL) were added methyl(E)-3-(3,5-difluoro-4-formylphenyl) acrylate (1.69 g, 7.49 mmol) andAcOH (0.2 mL, 3.5 mmol) and the mixture was heated at 90° C. for 5 h.The reaction mixture was diluted with EtOAc and washed with water. Theorganic layer was separated and the aqueous layer was extracted withEtOAc (2×20 mL). The combined organic phase was dried over sodiumsulfate, filtered and concentrated. The resultant residue was purifiedby flash chromatography (SiO₂, 20% ethyl acetate/hexane) to afford((E)-methyl3-(3,5-difluoro-4-((1R,3R)-2-(2-fluoro-2-methylpropyl)-7-hydroxy-3-methyl-2,3,4,9-tetrahydro-1H-pyrido[3,4-b]indol-1-yl)phenyl)acrylate(1.2 g, 19.4 mmol, 37% yield) as an off white solid. MS (ESI) m/z 473.38[M+H]⁺.

Step 7

To a stirred solution of (E)-methyl3-(3,5-difluoro-4-((1R,3R)-2-(2-fluoro-2-methylpropyl)-7-hydroxy-3-methyl-2,3,4,9-tetrahydro-1H-pyrido[3,4-b]indol-1-yl)phenyl)acrylate(800 mg, 16.9 mmol) in THF/water (1:1, 15 mL) at 0° C. was added LiOH(232 mg, 10.2 mmol). The mixture was stirred at rt for 5 h. The organicvolatiles were removed under reduced pressure. The residue was acidifiedwith an aqueous hydrogen chloride solution (1N) at 0° C. The reactionmixture was diluted with EtOAc and washed with water. The combinedorganic layer was dried over sodium sulfate, filtered and concentrated.The crude compound was purified by reverse phase prep HPLC [mobilephase: (A) 10 mM aqueous ammonium bicarbonate, (B) Acetonitrile; Flow:19 mL/min. Column: Inertsil C₁₈ (250×20 mm), 5 m] to afford the ammoniumsalt of(E)-3-(3,5-difluoro-4-((1R,3R)-2-(2-fluoro-2-methylpropyl)-7-hydroxy-3-methyl-2,3,4,9-tetrahydro-1H-pyrido[3,4-b]indol-1-yl)phenyl)acrylic acid (40 mg, 0.08 mmol, 5% yield) as an orange solid afterlyophilization. ¹H NMR (300 MHz, DMSO-d₆) δ 10.2 (s, 1H), 7.42 (d,J=15.0 Hz, 1H), 7.38 (d, J=10.5 Hz, 2H), 7.15 (d, J=8.7 Hz, 1H), 6.64(d, J=15.8 Hz, 1H), 6.57 (d, J=2.1 Hz, 1H), 6.47 (dd, J=8.1, 1.8 Hz,1H), 5.13 (s, 1H), 3.53-3.45 (m, 1H), 2.91-2.79 (m, 2H), 2.47-2.26 (m,2H), 1.19 (d, J=20.4 Hz, 3H), 1.12 (d, J=21.0 Hz, 3H), 1.03 (d, J=6.3Hz, 3H), carboxylic acid and phenolic protons were not observed; MS(ESI) m/z 458.97 [M+H]⁺.

Example 16A(E)-3-(3,5-Difluoro-4-((1R,3R)-2-((3-fluorooxetan-3-yl)methyl)-3-methyl-2,3,4,9-tetrahydro-1H-pyrido[3,4-b]indol-1-yl)phenyl)acrylicacid (16A)

Step 1

To a stirred solution of (R)-1-(1H-indol-3-yl)propan-2-amine (0.15 g,0.861 mmol) in dioxane (2.87 ml) was added (3-fluorooxetan-3-yl)methyltrifluoromethanesulfonate (0.226 g, 0.947 mmol) andN,N-diisopropylethylamine (0.300 ml, 1.722 mmol) and the mixture wasstirred at 90° C. for 4 h. The reaction mixture was diluted with ethylacetate (10 mL) and washed with saturated aqueous NaHCO₃ solution (5mL). The combined organics were dried over sodium sulfate, filtered andconcentrated. The resultant residue was purified by flash chromatography(SiO₂, 60-80% ethyl acetate/hexane) to afford(R)—N-((3-fluorooxetan-3-yl)methyl)-1-(1H-indol-3-yl)propan-2-amine(0.18 g, 80% yield). MS (APCI) m/z 263.15 [M+H]⁺.

Step 2

To a stirred solution of(R)—N-((3-fluorooxetan-3-yl)methyl)-1-(1H-indol-3-yl)propan-2-amine(0.10 g, 0.381 mmol) in toluene (1.91 ml) were added (E)-ethyl3-(3,5-difluoro-4-formylphenyl)acrylate (0.097 g, 0.404 mmol)acetic acid(0.046 g, 0.762 mmol). The mixture was stirred at 90° C. for 5 h. Thereaction mixture was diluted with EtOAc, the organic layer was separatedand then washed with water. The combined organic layer was dried oversodium sulfate, filtered and concentrated. The resulting residue waspurified by flash chromatography (SiO₂, 15-60% ethyl acetate/hexane) toafford ethyl(E)-3-(3,5-difluoro-4-((1R,3R)-2-((3-fluorooxetan-3-yl)methyl)-3-methyl-2,3,4,9-tetrahydro-1H-pyrido[3,4-b]indol-1-yl)phenyl)acrylate(0.11 g, 60% yield) as a pale yellow solid. MS (APCI) m/z 485.2 [M+H]⁺.

Step 3

To a stirred solution of (E)-ethyl3-(3,5-difluoro-4-((1R,3R)-2-((3-fluorooxetan-3-yl)methyl)-3-methyl-2,3,4,9-tetrahydro-1H-pyrido[3,4-b]indol-1-yl)phenyl)acrylate(0.08 g, 0.165 mmol) in a mixture of methanol:THF:water (1:1:1, total of3 mL) at 0° C. was added sodium hydroxide (0.020 g, 0.495 mmol) and themixture was stirred at rt for 2 h. The reaction mixture was concentratedand the residue was acidified with an aqueous solution of citric acid(1M) at 0° C. to adjust pH to 5. The precipitate that formed wasfiltered, washed with water and dried. The resulting solid was dissolvedin DMSO (1 mL) and purified by reversed phase HPLC, using 10-50%acetonitrile (contains 0.1% formic acid) in water (contains 0.1% formicacid) to afford(E)-3-(3,5-difluoro-4-((1R,3R)-2-((3-fluorooxetan-3-yl)methyl)-3-methyl-2,3,4,9-tetrahydro-1H-pyrido[3,4-b]indol-1-yl)phenyl)acrylicacid (0.035 g, 46% yield) after lyophilization ¹H NMR (400 MHz, DMSO-d₆)δ 12.6 (s, 1H), 10.6 (s, 1H), 7.54 (d, J=16 Hz, 1H), 7.47 (d, J=8 Hz,2H), 7.42 (d, J=8 Hz, 1H), 7.20 (d, J=8 Hz, 1H), 7.03-6.92 (m, 2H), 6.67(d, J=16 Hz, 1H), 5.28 (s, 1H), 4.61-4.44 (m, 3H), 4.35-4.25 (m, 1H),2.87-2.73 (m, 2H), 2.63-2.56 (m, 2H), 1.24-1.14 (m, 2H), 1.12 (d, J=8Hz, 3H); MS (APCI) m/z 457.17 [M+H]⁺.

Example 17A((E)-3-(3,5-Difluoro-4-((1R,3R)-3-methyl-2-(oxetan-3-ylmethyl)-2,3,4,9-tetrahydro-1H-pyrido[3,4-b]indol-1-yl)phenyl)acrylicacid (17A)

Step 1

To a stirred solution of (R)-1-(1H-indol-3-yl)propan-2-amine (0.15 g,0.861 mmol) in dioxane (2.87 ml) were added oxetan-3-ylmethyltrifluoromethanesulfonate (0.218 g, 0.990 mmol) andN,N-diisopropylethylamine (0.330 ml, 1.89 mmol). The mixture was stirredat 90° C. for 4 h. The reaction mixture was diluted with ethyl acetate(10 mL) and washed with saturated aqueous NaHCO₃ solution (5 mL). Thecombined organic layers were dried over sodium sulfate and concentrated.The resulting residue was purified by flash chromatography (SiO₂, 0-10%MeOH in DCM) to afford(R)-1-(1H-indol-3-yl)-N-(oxetan-3-ylmethyl)propan-2-amine (0.11 g, 0.450mmol, 52% yield) MS (APCI) m/z 245.16 [M+H]+.

Step 2

To a stirred solution of(R)-1-(1H-indol-3-yl)-N-(oxetan-3-ylmethyl)propan-2-amine (0.064 g,0.262 mmol) in toluene (1.3 ml) were added (E)-ethyl3-(3,5-difluoro-4-formylphenyl)acrylate (0.067 g, 0.278 mmol) and aceticacid (0.031 g, 0.524 mmol) The reaction was stirred at 90° C. for 5 h.The reaction mixture was diluted with EtOAc and washed with water. Thecombined organic phase was dried over sodium sulfate, filtered andconcentrated. The resulting residue was purified by flash chromatography(SiO₂, 15-60% EtOAc in hexane) to afford ethyl(E)-3-(3,5-difluoro-4-((1R,3R)-3-methyl-2-(oxetan-3-ylmethyl)-2,3,4,9-tetrahydro-1H-pyrido[3,4-b]indol-1-yl)phenyl)acrylate(0.061 g, 0.131 mmol, 50% yield) as an pale yellow solid. MS (APCI) m/z467.21 [M+H]⁺.

Step 3

To a stirred solution of (E)-ethyl3-(3,5-difluoro-4-((1R,3R)-3-methyl-2-(oxetan-3-ylmethyl)-2,3,4,9-tetrahydro-1H-pyrido[3,4-b]indol-1-yl)phenyl)acrylate(0.06 g, 0.129 mmol) in a mixture of methanol:THF:water (1:1:1, total of3 mL) at 0° C. was added sodium hydroxide (0.015 g, 0.386 mmol). Thereaction mixture was stirred at rt for 2 h and then concentrated. Theresulting residue was acidified with a aqueous solution of citric acid(1M) at 0° C. to carefully adjust pH to 5. The precipitate that formedwas dissolved in EtOAc. The organic phase was washed with water, driedover sodium sulfate, filtered and concentrated. The resulting solid wasdissolved in DMSO (1 mL) and purified by reversed-phase HPLC, using10-60% acetonitrile (contains 0.1% formic acid) in water (contains 0.1%formic acid). The resulting fractions were lyophilized under reducedpressure to afford(E)-3-(3,5-difluoro-4-((1R,3R)-3-methyl-2-(oxetan-3-ylmethyl)-2,3,4,9-tetrahydro-1H-pyrido[3,4-b]indol-1-yl)phenyl)acrylicacid (0.009 g, 16% yield)¹H NMR (400 MHz, DMSO-d₆) δ 12.6 (s, 1H), 10.6(s, 1H), 7.55 (d, J=16 Hz, 1H), 7.48 (d, J=8 Hz, 2H), 7.40 (d, J=8 Hz,1H), 7.20 (d, J=8 Hz, 1H), 7.02-6.92 (m, 2H), 6.67 (d, J=16 Hz, 1H),5.10 (s, 1H), 4.62-4.51 (m, 2H), 4.16 (t, J=5.9 Hz, 1H), 3.93 (t, J=5.9Hz, 1H), 3.21-3.11 (m, 1H), 3.02-2.90 (m, 2H), 2.86-2.76 (m, 1H),2.64-2.53 (m, 2H), 1.07 (d, J=4 Hz, 3H); MS (APCI) m/z 439.18 [M+H]⁺.

Example 18A(E)-3-(3,5-Difluoro-4-((1R,3R)-3-methyl-2-((3-methyloxetan-3-yl)methyl)-2,3,4,9-tetrahydro-1H-pyrido[3,4-b]indol-1-yl)phenyl)acrylicacid (18A)

Step 1

To a stirred solution of (R)-1-(1H-indol-3-yl)propan-2-amine (0.22 g,1.26 mmol) in dichloromethane (5 ml) was added HATU (0.386 g, 1.64 mmol)and N,N-diisopropylethylamine (0.506 ml, 2.90 mmol) at rt and themixture was stirred for 10 min. 3-Methyloxetane-3-carboxylic acid (0.161g, 1.39 mmol) was added and the reaction was stirred at rt for 16 h. Thereaction mixture was diluted with EtOAc and washed with an aqueoussaturated NaHCO₃ solution. The organic layer was separated, dried overNa₂SO₄, filtered and concentrated. The resulting residue was purified byflash chromatography (SiO₂, 0-10% MeOH in DCM) to afford(R)—N-(1-(1H-indol-3-yl)propan-2-yl)-3-methyloxetane-3-carboxamide (0.30g, 1.10 mmol, 87% yield) MS (APCI) m/z 273.15 [M+H]⁺.

Step 2

To a stirred solution of(R)—N-(1-(1H-indol-3-yl)propan-2-yl)-3-methyloxetane-3-carboxamide (0.22g, 0.808 mmol) in THF (3 ml) was added LAH (2.83 ml, 5.65 mmol, 2M inTHF) dropwise at 0° C. and the mixture was heated to reflux for 48hours. The completion of the reaction (as monitored by TLC) was gaugedby consumption of starting material. The reaction mixture was quenchedslowly with ice cold water (0.25 mL), an aqueous solution of 15% NaOHsolution (0.50 mL) and water (0.75 mL). The resulting residue wasextracted with EtOAc (2×20 mL) and the separated organic phase was driedover Na₂SO₄, filtered, and concentrated. The resulting residue waspurified by column chromatography [SiO₂, 0-50% DCM/(DCM:7M ammonia inmethanol (9:1 v/v))] to afford(R)-1-(1H-indol-3-yl)-N-((3-methyloxetan-3-yl)methyl)propan-2-amine(0.12 g, 57% yield) MS (APCI) m/z 259.17 [M+H]⁺.

Step 3

To a stirred solution of(R)-1-(1H-indol-3-yl)-N-((3-methyloxetan-3-yl)methyl)propan-2-amine(0.10 g, 0.387 mmol) in toluene (1.91 mL) were added (E)-ethyl3-(3,5-difluoro-4-formylphenyl)acrylate (0.099 g, 0.410 mmol) and aceticacid (0.046 g, 0.774 mmol). The reaction mixture was stirred at 90° C.for 5 h and cooled to rt. The mixture was diluted with EtOAc and washedwith water. The combined organic layers were dried over sodium sulfate,filtered and concentrated. The resulting residue was purified by flashchromatography (SiO₂, 15-60% ethyl acetate in hexane) to afford ethyl(E)-3-(3,5-difluoro-4-((1R,3R)-3-methyl-2-((3-methyloxetan-3-yl)methyl)-2,3,4,9-tetrahydro-1H-pyrido[3,4-b]indol-1-yl)phenyl)acrylate(0.11 g, 59% yield) as a pale yellow solid. MS (APCI) m/z 481.22 [M+H]⁺.

Step 4

To a stirred solution of (E)-ethyl3-(3,5-difluoro-4-((1R,3R)-3-methyl-2-((3-methyloxetan-3-yl)methyl)-2,3,4,9-tetrahydro-1H-pyrido[3,4-b]indol-1-yl)phenyl)acrylate(0.061 g, 0.127 mmol) in a mixture of methanol:THF:water (1:1:1, totalof 3 mL) at 0° C. was added sodium hydroxide (0.020 g, 0.495 mmol). Thereaction was stirred at rt for 2 h. The resulting mixture wasconcentrated under reduced pressure and the residue was acidified withan aqueous solution of citric acid (1M) at 0° C. to adjust pH to 5. Theprecipitate that formed was filtered, washed with water and dried. Theresulting solid was dissolved in DMSO (1 mL) and purified by reversedphase HPLC using 10-60% acetonitrile (contains 0.1% formic acid) inwater (contains 0.1% formic acid) to afford(E)-3-(3,5-difluoro-4-((1R,3R)-3-methyl-2-((3-methyloxetan-3-yl)methyl)-2,3,4,9-tetrahydro-1H-pyrido[3,4-b]indol-1-yl)phenyl)acrylicacid (0.03 g, 52% yield) after lyophilization. ¹H NMR (400 MHz, DMSO-d₆)δ 10.6 (s, 1H), 7.54 (d, J=16 Hz, 1H), 7.46 (d, J=8 Hz, 2H), 7.40 (d,J=8 Hz, 1H), 7.18 (d, J=8 Hz, 1H), 7.03-6.92 (m, 2H), 6.66 (d, J=16 Hz,1H), 5.07 (s, 1H), 4.40 (d, J=8 Hz, 1H), 4.16 (t, J=8 Hz, 1H), 4.05-4.00(m, 1H), 3.08-2.83 (m, 4H), 2.63-2.55 (m, 1H), 2.36-2.30 (m, 1H), 1.21(s, 3H), 1.03 (d, J=4 Hz, 3H), proton of carboxylic acid not observed;MS (APCI) m/z 453.19 [M+H]⁺.

Example 19A(E)-3-(4-((3S)-3-(Difluoromethyl)-2-(tetrahydrofuran-3-yl)-2,3,4,9-tetrahydro-1H-pyrido[3,4-b]indol-1-yl)-3,5-difluorophenyl)acrylicacid (19A)

Step 1

To a stirred solution of (S)-2-amino-3-(1H-indol-3-yl)propan-1-ol (0.91g, 4.78 mmol) in DCM (12 ml) were added imidazole (0.977 g, 14.4 mmol)and a solution of t-butylchlorodiphenylsilane (1.578 g, 5.74 mmol) inDCM (6 mL) at 0° C. The mixture was stirred for 18 h at rt. A saturatedaqueous NaHCO₃ solution was added and the mixture was extracted withDCM. The organic layers were separated, washed with brine, dried(MgSO₄), filtered and concentrated. The residue was purified by flashchromatography (SiO₂, 0-15% methanol in DCM) to afford(S)-1-((tert-butyldiphenylsilyl)oxy)-3-(1H-indol-3-yl)propan-2-amine(1.69 g, 3.94 mmol, 82% yield) MS (APCI) m/z 429.23 [M+H]⁺.

Step 2

To a stirred solution of(S)-1-((tert-butyldiphenylsilyl)oxy)-3-(1H-indol-3-yl)propan-2-amine(1.3 g, 3.03 mmol) in ethanol (10 mL) was added dihydrofuran-3(2H)-one(0.313 g, 3.64 mmol) and the mixture was heated at 50° C. for 1 h. Thereaction was cooled to 0° C. Sodium borohydride (0.172 g, 4.55 mmol) wasadded and after stirring for 2 h, the mixture was concentrated. Ethylacetate and a saturated solution of ammonium chloride were added. Theorganic layer was separated, dried over sodium sulfate, filtered andconcentrated. The residue was purified by flash chromatography (SiO₂,0-10% MeOH in DCM) to obtainN—((S)-1-((tert-butyldiphenylsilyl)oxy)-3-(1H-indol-3-yl)propan-2-yl)tetrahydrofuran-3-amine(1.20 g, 2.41 mmol, 79% yield). MS (APCI) m/z 499.3 [M+H]⁺.

Step 3

To a stirred solution ofN—((S)-1-((tert-butyldiphenylsilyl)oxy)-3-(1H-indol-3-yl)propan-2-yl)tetrahydrofuran-3-amine(0.75 g, 1.50 mmol) in toluene (3 mL) were added (E)-ethyl3-(3,5-difluoro-4-formylphenyl)acrylate (0.43 g, 1.80 mmol) and aceticacid (0.18 g, 3.01 mmol) The reaction mixture was heated at 85° C. for 4h and, after cooling to rt, was diluted with EtOAc and washed withwater. The organic layer was separated, dried over sodium sulfate,filtered and concentrated. The resulting residue was purified by flashchromatography (SiO₂, 0-30% ethyl acetate/hexanes) to afford (E)-ethyl3-(4-((1R,3S)-3-(((tert-butyldiphenylsilyl)oxy)methyl)-2-(tetrahydrofuran-3-yl)-2,3,4,9-tetrahydro-1H-pyrido[3,4-b]indol-1-yl)-3,5-difluorophenyl)acrylate(0.50 g, 0.694 mmol, 46% yield) as a mixture of isomers. MS (APCI) m/z721.32 [M+H]⁺.

Step 4

To a stirred solution of (E)-ethyl3-(4-((1R,3S)-3-(((tert-butyldiphenylsilyl)oxy)methyl)-2-(tetrahydrofuran-3-yl)-2,3,4,9-tetrahydro-1H-pyrido[3,4-b]indol-1-yl)-3,5-difluorophenyl)acrylate(0.80 g, 1.110 mmol) in THF (3.70 mL) was added dropwise a solution oftetrabutylammonium fluoride (1.33 ml, 1.33 mmol, 1M in THF). The mixturewas stirred at rt for 36 h. THF was removed under reduced pressure andDCM was added. The organic layer was washed with water, separated, andconcentrated. The resulting residue was purified by flash chromatography(SiO₂, 20-60% ethyl acetate/hexanes) to afford (E)-ethyl3-(3,5-difluoro-4-((1R,3S)-3-(hydroxymethyl)-2-(tetrahydrofuran-3-yl)-2,3,4,9-tetrahydro-1H-pyrido[3,4-b]indol-1-yl)phenyl)acrylate(0.30 g, 0.622 mmol, 56% yield) as a mixture of isomers. MS (APCI) m/z483.20 [M+H]⁺.

Step 5

To a solution under nitrogen of (E)-ethyl3-(3,5-difluoro-4-((1R,3S)-3-(hydroxymethyl)-2-(tetrahydrofuran-3-yl)-2,3,4,9-tetrahydro-1H-pyrido[3,4-b]indol-1-yl)phenyl)acrylate(0.10 g, 0.207 mmol) in dimethyl sulfoxide (0.80 mL) was added IBX(0.073 g, 0.259 mmol) and the mixture was stirred for 16 hours at roomtemperature. The mixture was diluted with EtOAc and washed successivelywith an aqueous solution of 5% sodium bicarbonate, water and brine. Theorganic extracts were dried over sodium sulfate, filtered andconcentrated to give crude (E)-ethyl3-(3,5-difluoro-4-(3S)-(3-formyl-2-(tetrahydrofuran-3-yl)-2,3,4,9-tetrahydro-1H-pyrido[3,4-b]indol-1-yl)phenyl)acrylate(0.06 g, 0.125 mmol, 60% yield) as a mixture of isomers. MS (APCI) m/z483.20 [M+H]⁺.

Step 6

To a stirred solution of (E)-ethyl3-(3,5-difluoro-4-(3S)-((3-formyl-2-(tetrahydrofuran-3-yl)-2,3,4,9-tetrahydro-1H-pyrido[3,4-b]indol-1-yl)phenyl)acrylate(0.055 g, 0.114 mmol) in DCM (0.382 ml) was added Deoxofluor (0.085 ml,0.229 mmol) dropwise at 0° C. The mixture was stirred at rt for 3 h. Asaturated aqueous solution of ammonium chloride was added and theresulting mixture was extracted with DCM (5×10 mL). The organic layerwas separated, dried over sodium sulfate and filtered. The solvent wasevaporated and crude residue was purified by flash chromatography (SiO₂,20-50% ethyl acetate/hexane) to obtain (E)-ethyl3-(4-((3S)-3-(difluoromethyl)-2-(tetrahydrofuran-3-yl)-2,3,4,9-tetrahydro-1H-pyrido[3,4-b]indol-1-yl)-3,5-difluorophenyl)acrylate(0.010 g, 17% yield) MS (APCI) m/z 503.19 [M+H]+.

Step 7

To a stirred solution of (E)-ethyl3-(4-((3S)-3-(difluoromethyl)-2-(tetrahydrofuran-3-yl)-2,3,4,9-tetrahydro-1H-pyrido[3,4-b]indol-1-yl)-3,5-difluorophenyl)acrylate(0.010 g, 0.020 mmol) in a mixture of methanol:THF:water (1:1:1, totalof 3 mL) at 0° C. was added sodium hydroxide (3.98 mg, 0.100 mmol). Themixture was stirred at rt for 2 h and then concentrated. The residue wastreated with an aqueous solution of citric acid (1M) at 0° C. to adjustpH to 5. The precipitate was extracted with EtOAc and the organicsolution was concentrated. The resulting solid was dissolved in DMSO (1mL) and purified by reversed phase HPLC using 10-50% acetonitrile(containing 0.1% formic acid) in water (containing 0.1% formic acid) toafford(E)-3-((3S)-4-(3-(difluoromethyl)-2-(tetrahydrofuran-3-yl)-2,3,4,9-tetrahydro-1H-pyrido[3,4-b]indol-1-yl)-3,5-difluorophenyl)acrylicacid (0.004 g, 8.43 mol, 42% yield) after lyophilization. MS (APCI) m/z475.16 [M+H]+.

Example 20(E)-3-(3,5-Difluoro-4-(2′-(tetrahydrofuran-3-yl)-1′,2′,4′,9′-tetrahydrospiro[cyclopropane-1,3′-pyrido[3,4-b]indol]-1′-yl)phenyl)acrylicacid (20)

Step 1

To a solution of 2-(1H-indol-3-yl)acetonitrile (2 g, 12.81 mmol) andmethyltitanium triisopropoxide (18.57 ml, 18.57 mmol, 1M in THF) in THF(85 ml) was added dropwise ethylmagnesium bromide solution (6.40 ml,19.1 mmol, 3M in diethyl ether) under argon. After stirring for 2 h,boron trifluoride diethyl ether complex (3.16 ml, 25.6 mmol) was addeddropwise and the mixture was stirred for 45 min at rt. An aqueoussolution of HCl (120 mL, 1M) was added followed by EtOAc (100 mL) and anaqueous solution of NaOH (120 mL, 3M). The aqueous phase was extractedwith EtOAc (3×30 mL). The organic phase was dried over magnesiumsulfate, filtered and concentrated. The crude material was purified byflash chromatography [SiO₂, 0-50% DCM/(DCM:7M ammonia in MeOH (9:1v/v))] to obtain 1-((1H-indol-3-yl)methyl)cyclopropane-1-amine (0.90 g,37% yield). MS (APCI) m/z 187.12 [M+H]⁺.

Step 2

To a stirred solution of 1-((1H-indol-3-yl)methyl)cyclopropanamine (0.30g, 1.61 mmol) in DCE (5.37 ml) was added dihydrofuran-3(2H)-one (0.180g, 2.094 mmol) and sodium triacetoxyborohydride (0.683 g, 3.22 mmol) at0° C. After being stirred at rt for 2 h, the mixture was concentrated.Ethyl acetate (30 mL) and a saturated aqueous solution of ammoniumchloride were added. The organic phase was separated, dried over sodiumsulfate and concentrated. The residue was purified by flashchromatography (SiO₂, 0-50% DCM/(DCM:7M ammonia in MeOH (9:1 v/v))) toafford N-(1-((1H-indol-3-yl)methyl)cyclopropyl)tetrahydrofuran-3-amine(0.27 g, 1.05 mmol, 65% yield) as a yellowish-white solid. MS (APCI) m/z257.16 [M+H]⁺.

Step 3

To a stirred solution ofN-(1-((1H-indol-3-yl)methyl)cyclopropyl)tetrahydrofuran-3-amine (0.078g, 0.304 mmol) in toluene (1 mL) were added (E)-ethyl3-(3,5-difluoro-4-formylphenyl)acrylate (0.08 g, 0.335 mmol) and aceticacid (0.04 g, 0.61 mmol). The reaction was stirred at 90° C. for 4 h,cooled to rt, diluted with EtOAc and washed with water. The organiclayer was separated, dried over sodium sulfate, filtered andconcentrated. The residue was purified by flash chromatography (SiO₂,60-100% EtOAc in hexane) to afford (E)-ethyl3-(3,5-difluoro-4-(2′-(tetrahydrofuran-3-yl)-1′,2′,4′,9′-tetrahydrospiro[cyclopropane-1,3′-pyrido[3,4-b]indol]-1′-yl)phenyl)acrylate(0.06 g, 41% yield) as a mixture of isomers. MS (APCI) m/z 479.21[M+H]⁺.

Step 4

To a stirred solution of (E)-ethyl3-(3,5-difluoro-4-(2′-(tetrahydrofuran-3-yl)-1′,2′,4′,9′-tetrahydrospiro[cyclopropane-1,3′-pyrido[3,4-b]indol]-1′-yl)phenyl)acrylate(0.07 g, 0.146 mmol) in a mixture of methanol:THF:water (1:1:1, total of3 mL) at 0° C. was added sodium hydroxide (0.075 g, 1.873 mmol). Themixture was stirred at rt for 2 h and then concentrated. The residue wasacidified with an aqueous solution of citric acid (1M) at 0° C. toadjust pH to 5. The resulting mixture was extracted with EtOAc andwashed with water. The organic layer was concentrated and dried underreduced pressure to afford(E)-3-(3,5-difluoro-4-(2′-(tetrahydrofuran-3-yl)-1′,2′,4′,9′-tetrahydrospiro[cyclopropane-1,3′-pyrido[3,4-b]indol]-1′-yl)phenyl)acrylicacid (0.025 g, 38% yield) as a mixture of isomers. MS (APCI) m/z 451.18[M+H]⁺.

Example 21A(E)-3-(3,5-Difluoro-4-((1R,3R)-6-fluoro-2-(2-fluoro-2-methylpropyl)-3-methyl-2,3,4,9-tetrahydro-1H-pyrido[3,4-b]indol-1-yl)phenyl)acrylicacid (21A)

Step 1

To a suspension of(R)-2-(((9H-fluoren-9-yl)methoxy)carbonylamino)propanoic acid (10 g,32.2 mmol) in DCM (100 mL) at 0° C. was added oxalyl chloride (4.3 mL,48.2 mmol) followed by a catalytic amount of DMF (0.18 mL, 10 mol %).The mixture was stirred at rt for 4 h and concentrated. The resultantresidue was treated with toluene and concentrated (2×50 mL) to affordcrude compound (9H-fluoren-9-yl)methyl1-chloro-1-oxopropan-2-ylcarbamate (22 g, crude weight) as a pale yellowsolid.

Step 2

Ethylmagnesium bromide (30.5 mL, 91.7 mmol, 3.0M solution in Et₂O) wasadded dropwise to a solution of 5-fluoro-1H-indole (4.13 g, 44.8 mmol)in DCM (100 mL) at 0° C. over a period of 0.5 h under an atmosphere ofargon. After being stirred at rt for 1 h, the reaction mixture wascooled to 0° C. and treated with a solution of (9H-fluoren-9-yl)methyl1-chloro-1-oxopropan-2-ylcarbamate (15 g, 45.59 mmol) in DCM (100 mL)under an atmosphere of argon. After being stirred at rt for another 12h, the resulting mixture was then cooled to 0° C. and quenched by 2N HCl(100 mL). The organic layer was separated and the aqueous layer wasextracted with CH₂Cl₂ (2×200 mL). The combined organic layers werewashed with water and brine, dried over sodium sulfate, filtered andconcentrated. The crude product was triturated with 10% Et₂O inn-pentane to afford (9H-fluoren-9-yl)methyl(R)-(1-(5-fluoro-1H-indol-3-yl)-1-oxopropan-2-yl)carbamate (3.99 g, 9.32mmol, 31% yield) as a brown solid. MS (ESI) m/z 429.04 [M+H]⁺.

Step 3

To a stirred solution of (9H-fluoren-9-yl)methyl(R)-(1-(5-fluoro-1H-indol-3-yl)-1-oxopropan-2-yl)carbamate (950 mg, 2.21mmol) in a mixture of acetonitrile/IPA (4:1, total of 10 mL) was addedsodium borohydride (839 mg, 22.2 mmol) in several portions under anargon atmosphere at 0° C. The mixture was heated at reflux for 15 h.After consumption of starting material as indicated by TLC, the reactionmixture was cooled back to 0° C. Methanol (5 mL) was added to destroyexcess reagent and the mixture was stirred at rt for 30 min. Water (100mL) was added and the aqueous phase was extracted with ethyl acetate(3×100 mL). The combined organic layers were washed with water andbrine, dried over sodium sulfate, filtered and concentrated. The residuewas triturated with pentane to afford(R)-1-(5-fluoro-1H-indol-3-yl)propan-2-amine (700 mg, 3.64 mmol, crude)as a brown solid. MS (ESI) m/z 193.00 [M+H]⁺.

Step 4

To a stirred solution of (R)-1-(5-fluoro-1H-indol-3-yl)propan-2-amine(700 mg, 3.64 mmol) in 1,4-dioxane (8 mL) was added2-fluoro-2-methylpropyl trifluoromethanesulfonate (898 mg, 4.0 mmol) andN—N-diisopropylethylamine (0.95 mL, 5.46 mmol) at 0° C. After beingstirred at 90° C. for 5 h, the reaction was cooled to rt and quenchedwith water (20 mL). The mixture was extracted with ethyl acetate (2×50mL). The combined organic layers were dried over sodium sulfate,filtered and concentrated. The resultant residue was purified by flashchromatography (SiO₂, 50% ethyl acetate in hexanes) to afford(R)-2-fluoro-N-(1-(5-fluoro-1H-indol-3-yl)propan-2-yl)-2-methylpropan-1-amine(340 mg, 1.27 mmol, 35% yield). MS (ESI) m/z 266.90 [M+H]⁺.

Step 5

To a stirred solution of(R)-2-fluoro-N-(1-(5-fluoro-1H-indol-3-yl)propan-2-yl)-2-methylpropan-1-amine(340 mg, 1.27 mmol) in toluene (5 mL) were added methyl(E)-3-(3,5-difluoro-4-formylphenyl) acrylate (292 mg, 1.29 mmol) andAcOH (0.1 mL, 1.75 mmol) at 0° C. After being stirred at 90° C. for 16h, the reaction mixture was cooled to rt, diluted with ethyl acetate,and washed with water. The organic layer was separated. The aqueouslayer was extracted with ethyl acetate (2×20 mL). The combined organiclayers were dried over sodium sulfate, filtered and concentrated. Theresultant residue was purified by flash column chromatography (SiO₂, 20%ethyl acetate in hexanes) to afford (E)-methyl3-(3,5-difluoro-4-((1R,3R)-6-fluoro-2-(2-fluoro-2-methylpropyl)-3-methyl-2,3,4,9-tetrahydro-1H-pyrido[3,4-b]indol-1-yl)phenyl)acrylate_(340mg, 0.71 mmol, 56% yield) as a yellow solid. MS (ESI) m/z 475.57 [M+H]⁺.

Step 6

To a stirred solution of (E)-methyl3-(3,5-difluoro-4-((1R,3R)-6-fluoro-2-(2-fluoro-2-methylpropyl)-3-methyl-2,3,4,9-tetrahydro-1H-pyrido[3,4-b]indol-1-yl)phenyl)acrylate(240 mg, 0.50 mmol) in THF/water (1:1, total of 15 mL) was addedLiOH.H₂O (85 mg, 2.02 mmol) at 0° C. After being stirred at rt for 5 h,the solvents were removed under reduced pressure. The residue wasacidified with a saturated citric acid solution at 0° C. and extractedwith ethyl acetate (3×20 mL). The combined organic layers were driedover sodium sulfate, filtered and concentrated. The resultant residuewas triturated with 10% Et₂O/n-pentane to give(E)-3-(3,5-difluoro-4-((1R,3R)-6-fluoro-2-(2-fluoro-2-methylpropyl)-3-methyl-2,3,4,9-tetrahydro-1H-pyrido[3,4-b]indol-1-yl)phenyl)acrylicacid (151 mg, 0.32 mmol, 65% yield) as a pale yellow solid. [α]²⁵ _(D)−40.00 (c 0.5, MeOH); Melting point: 128-130° C. ¹H NMR (300 MHz,DMSO-d₆) δ 12.6 (br s, 1H), 10.72 (s, 1H), 7.54 (d, J=15.9 Hz, 1H), 7.46(d, J=10.2 Hz, 2H), 7.18-7.14 (m, 2H), 6.83 (ddd, J=9.6, 7.2, 2.1 Hz,1H), 6.67 (d, J=15.9 Hz, 1H), 5.21 (s, 1H), 3.51-3.47 (m, 1H), 2.92-2.81(m, 2H), 2.58-2.50 (m, 1H), 2.33 (dd, J=23.1, 15.0 Hz, 1H), 1.20 (d,J=21.9 Hz, 3H), 1.12 (d, J=21.6 Hz, 3H), 1.05 (d, J=6.3 Hz, 3H); MS(ESI) m/z 461.53 [M+H]⁺.

Example 22(E)-3-(4-(2-(Bicyclo[1.1.1]pentan-1-ylmethyl)-3,3-dimethyl-2,3,4,9-tetrahydro-1H-pyrido[3,4-b]indol-1-yl)-3,5-difluorophenyl)acrylicacid (22)

Step 1

To a stirred solution of 1-(1H-indol-3-yl)-2-methylpropan-2-amine (0.31g, 1.65 mmol) in DCM (6.33 ml) were added HATU (0.504 g, 2.14 mmol) andN,N-diisopropylethylamine (0.574 ml, 3.29 mmol) at rt. The mixture wasstirred for 10 min at rt and bicyclo[1.1.1]pentane-1-carboxylic acid(0.203 g, 1.81 mmol) was added. After being stirred at rt for 16 h, thereaction mixture was diluted with EtOAc (15 mL) and washed withsaturated aqueous NaHCO₃ solution. The organic layer was separated,dried over Na₂SO₄, filtered and concentrated. The resulting residue waspurified by flash chromatography (SiO₂, 30-60% EtOAc in hexane) toaffordN-(1-(1H-indol-3-yl)-2-methylpropan-2-yl)bicyclo[1.1.1]pentane-1-carboxamide(0.36 g, 77% yield). MS (APCI) m/z 283.17 [M+H]⁺.

Step 2

To a stirred solution ofN-(1-(1H-indol-3-yl)-2-methylpropan-2-yl)bicyclo[1.1.1]pentane-1-carboxamide(0.36 g, 1.28 mmol) in THF (5.10 ml) was added LAH (5.19 ml, 10.38 mmol,2M LAH in THF) dropwise at 0° C. After being refluxed for 18 h, thereaction mixture was quenched sequentially with cold (0-5° C.) water(0.40 mL) slowly, then an aqueous solution of 15% NaOH (0.80 mL) andwater (1.2 mL). The resulting precipitate was extracted with EtOAc (2×20mL). The separated organic layers were dried over Na₂SO₄, filtered, andconcentrated under reduced pressure. The resulting residue was purifiedby flash chromatography (SiO₂, 0-50% DCM/(DCM:methanolic solution ofammonia (7M) (9:1 v/v))) to affordN-(bicyclo[1.1.1]pentan-1-ylmethyl)-1-(1H-indol-3-yl)-2-methylpropan-2-amine(0.14 g, 0.522 mmol, 41% yield). MS (APCI) m/z 269.19 [M+H]⁺.

Step 3

To a stirred solution ofN-(bicyclo[1.1.1]pentan-1-ylmethyl)-1-(1H-indol-3-yl)-2-methylpropan-2-amine(0.07 g, 0.261 mmol) in toluene (0.65 mL) were added (E)-ethyl3-(3,5-difluoro-4-formylphenyl)acrylate (0.069 g, 0.287 mmol) and aceticacid (0.031 g, 0.522 mmol) at 0° C. After being stirred at 90° C. for 5h, the reaction mixture was diluted with EtOAc and washed with water.The separated organic layers were dried over sodium sulfate, filteredand concentrated. The resulting residue was purified by flashchromatography (SiO₂, 0-15% ethyl acetate in hexane) to afford (E)-ethyl3-(4-(2-(bicyclo[1.1.1]pentan-1-ylmethyl)-3,3-dimethyl-2,3,4,9-tetrahydro-1H-pyrido[3,4-b]indol-1-yl)-3,5-difluorophenyl)acrylate(0.025 g, 0.051 mmol, 19% yield) as a pale yellow solid. MS (APCI) m/z491.24 [M+H]⁺.

Step 4

To a stirred solution of (E)-ethyl3-(4-(2-(bicyclo[1.1.1]pentan-1-ylmethyl)-3,3-dimethyl-2,3,4,9-tetrahydro-1H-pyrido[3,4-b]indol-1-yl)-3,5-difluorophenyl)acrylate(0.02 g, 0.041 mmol) in a mixture of methanol (1 mL), THF (1 mL) andwater (1 mL) was added sodium hydroxide (4.89 mg, 0.122 mmol) at 0° C.After being stirred at rt for 2 h, the mixture was concentrated underreduced pressure and the obtained residue was acidified with a solutionof citric acid (1M) at 0° C. to adjust pH to 5. The precipitate wasextracted with EtOAc and the organic phase was concentrated. Theresulting residue was dissolved in DMSO (1 mL) and purified byreversed-phase HPLC using 10-60% acetonitrile (contains 0.1% formicacid) in water (contains 0.1% formic acid) to obtain(E)-3-(4-(2-(bicyclo[1.1.1]pentan-1-ylmethyl)-3,3-dimethyl-2,3,4,9-tetrahydro-1H-pyrido[3,4-b]indol-1-yl)-3,5-difluorophenyl)acrylicacid (0.008 g, 41% yield) as a mixture of enantiomers. ¹H NMR (400 MHz,CDCl₃) δ 7.62 (br d, J=16.0 Hz, 1H), 7.53-7.45 (m, 1H), 7.22-7.18 (m,1H), 7.14-7.08 (m, 2H), 7.03 (d, J=8 Hz, 2H), 6.43 (d, J=16.0 Hz, 1H),5.14 (br s, 1H), 3.02 (br d, J=16.4 Hz, 1H), 2.91 (br d, J=13.9 Hz, 1H),2.63 (br d, J=14.9 Hz, 1H), 2.28 (br d, J=16.4 Hz, 1H), 2.19 (s, 1H),1.33-1.22 (m, 6H), 1.18 (br d, J=8 Hz, 3H), 1.03 (s, 3H) (missingcarboxylic acid and NH protons); MS (APCI) m/z 463.21 [M+H]⁺.

Example 23A and 23B(E)-3-(4-((1R,3R)-3-Ethyl-2-((S)-tetrahydrofuran-3-yl)-2,3,4,9-tetrahydro-1H-pyrido[3,4-b]indol-1-yl)-3,5-difluorophenyl)acrylicacid (23A)

(E)-3-(4-((1R,3R)-3-Ethyl-2-((R)-tetrahydrofuran-3-yl)-2,3,4,9-tetrahydro-1H-pyrido[3,4-b]indol-1-yl)-3,5-difluorophenyl)acrylicacid (23B)

Step 1

To a suspension of(R)-2-((((9H-fluoren-9-yl)methoxy)carbonyl)amino)butanoic acid (4 g,12.3 mmol) in DCM (40 mL) was added oxalyl dichloride (1.58 ml, 18.4mmol) followed by a catalytic amount of DMF (0.095 ml, 1.23 mmol) at 0°C. After being stirred at rt for 3 h, the reaction mixture wasconcentrated. The residue was treated twice with toluene andconcentrated (2×25 mL) to afford crude (9H-fluoren-9-yl)methyl(R)-(1-chloro-1-oxobutan-2-yl)carbamate (4.06 g, 96% yield) as a whitesolid.

Step 2

Under an argon atmosphere, ethylmagnesium bromide (8.54 ml, 25.6 mmol,3.0M solution in Et₂O) was added dropwise into a solution of 1H-indole(1 g, 8.54 mmol) in DCM (50 mL) at 0° C. over a period of 1 h. Afterbeing stirred at rt for another 1 h, the mixture was then cooled to 0°C. and treated with a solution of(R)-(9H-fluoren-9-yl)methyl(1-chloro-1-oxobutan-2-yl)carbamate (4.40 g,12.80 mmol) in DCM (30 mL). After being stirred at rt for 12 h, thereaction was quenched with aqueous HCl (200 mL, 2N) at 0° C. The organiclayer was separated and the aqueous layer was extracted with DCM (2×50mL). The combined organic layers were washed with water and brine, driedover sodium sulfate, filtered, and concentrated to afford(9H-fluoren-9-yl)methyl (R)-(1-(1H-indol-3-yl)-1-oxobutan-2-yl)carbamate(2.17 g, 5.11 mmol, 60% yield) as a brown liquid which was used directlyin the next reaction. MS (APCI) m/z 425.18 [M+H]⁺.

Step 3

To a solution of (R)-(9H-fluoren-9-yl)methyl(1-(1H-indol-3-yl)-1-oxobutan-2-yl)carbamate (2.2 g, 5.18 mmol) inacetonitrile/IPA (7:1, total of 32 mL) was added sodium borohydride(1.961 g, 51.8 mmol) under an argon atmosphere at 0° C. After beingrefluxed for 16 h, the mixture was cooled to 0° C., quenched withmethanol (25 ml), and stirred at rt for 15 min. The resulting mixturewas then concentrated under reduced pressure, diluted with EtOAc andwashed with water. The organic layer was dried over sodium sulfate,filtered and concentrated. The residue was purified by flashchromatography (SiO₂, 0-15% methanol in DCM) to afford(R)-1-(1H-indol-3-yl)butan-2-amine (0.47 g, 2.496 mmol, 48% yield). MS(APCI) m/z 189.13 [M+H]⁺.

Step 4

To a stirred solution of (R)-1-(1H-indol-3-yl)butan-2-amine (0.47 g,2.50 mmol) in ethanol (6 mL) were added dihydrofuran-3(2H)-one (0.258 g,3.00 mmol) and acetic acid (0.150 g, 2.50 mmol) at rt. The mixture wasstirred at rt for 3 h and then cooled to 0° C. Sodium borohydride (0.142g, 3.74 mmol) was added. After being stirred at 0° C.—rt for 16 h, thereaction mixture was concentrated, diluted with ethyl acetate (10 mL),and washed with saturated aqueous NH₄Cl solution (10 mL). The organiclayer was separated, dried over sodium sulfate, and concentrated. Theresidue was purified by flash chromatography (SiO₂, 0-10% methanol inDCM) to affordN—((R)-1-(1H-indol-3-yl)butan-2-yl)tetrahydrofuran-3-amine (0.20 g,31.0% yield) as a yellowish oil. MS (APCI) m/z 259.17 [M+H]⁺.

Step 5

To a stirred solution ofN—((R)-1-(1H-indol-3-yl)butan-2-yl)tetrahydrofuran-3-amine (0.20 g,0.774 mmol) in toluene (2 mL) were added (E)-ethyl3-(3,5-difluoro-4-formylphenyl)acrylate (0.223 g, 0.929 mmol) and aceticacid (0.093 g, 1.548 mmol) at 0° C. After being stirred at 90° C. for 5h, the reaction mixture was diluted with EtOAc and washed with water.The organic layer was separated, dried over sodium sulfate, andconcentrated. The resulting residue was purified by flash chromatography(SiO₂, 60-100% EtOAc in hexane) to afford (E)-ethyl3-(4-((1R,3R)-3-ethyl-2-(tetrahydrofuran-3-yl)-2,3,4,9-tetrahydro-1H-pyrido[3,4-b]indol-1-yl)-3,5-difluorophenyl)acrylate(0.22 g, 0.458 mmol, 59% yield) as a mixture of trans isomers. MS (APCI)m/z 481.22 [M+H]⁺.

Step 6

To a stirred solution of (E)-ethyl3-(4-((1R,3R)-3-ethyl-2-(tetrahydrofuran-3-yl)-2,3,4,9-tetrahydro-1H-pyrido[3,4-b]indol-1-yl)-3,5-difluorophenyl)acrylate(0.30 g, 0.624 mmol) in a mixture of methanol (1.5 mL), THF (1.5 mL) andwater (1.5 mL) was added sodium hydroxide (0.075 g, 1.87 mmol) at 0° C.After being stirred at rt for 2 h, the mixture was concentrated underreduced pressure to remove organic solvents. The residue was acidifiedwith aqueous citric acid (1M) at 0° C. to adjust pH to 5. Ethyl acetatewas added to dissolve the formed precipitate. The organic layer waswashed with water, separated, and concentrated. The residue was driedunder reduced pressure to afford(E)-3-(4-((1R,3R)-3-ethyl-2-(tetrahydrofuran-3-yl)-2,3,4,9-tetrahydro-1H-pyrido[3,4-b]indol-1-yl)-3,5-difluorophenyl)acrylicacid (0.22 g, 78% yield) as a mixture of trans isomers. MS (APCI) m/z453.19 [M+H]⁺.

Step 7

The mixture of isomers,(E)-3-(4-((1R,3R)-3-ethyl-2-(tetrahydrofuran-3-yl)-2,3,4,9-tetrahydro-1H-pyrido[3,4-b]indol-1-yl)-3,5-difluorophenyl)acrylicacid, was purified by reversed phase prep HPLC [Conditions: (A) 0.1%Formic Acid in water; (B) acetonitrile; Flow: 19 mL/min; Column: Xterra(19×150 mm) 5 μm; Gradient-(Time (min)/% B): 0.1/35; 11/35, 11.1/98,13/98, 13.1/10, 15/10] to afford(E)-3-(4-((1R,3R)-3-ethyl-2-((S)-tetrahydrofuran-3-yl)-2,3,4,9-tetrahydro-1H-pyrido[3,4-b]indol-1-yl)-3,5-difluorophenyl)acrylicacid (Designated as Peak 1) (20 mg, 0.04 mmol, 25% yield) and(E)-3-(4-((1R,3R)-3-ethyl-2-((R)-tetrahydrofuran-3-yl)-2,3,4,9-tetrahydro-1H-pyrido[3,4-b]indol-1-yl)-3,5-difluorophenyl)acrylicacid (Designated as Peak 2) (14 mg, 0.03 mmol, 17% yield) as an offwhite solid after lyophilization.

(E)-3-(4-((1R,3R)-3-ethyl-2-((S)-tetrahydrofuran-3-yl)-2,3,4,9-tetrahydro-1H-pyrido[3,4-b]indol-1-yl)-3,5-difluorophenyl)acrylicacid: ¹H NMR (400 MHz, DMSO-d₆) δ 10.2 (s, 1H), 7.48 (d, J=15.8 Hz, 1H),7.46 (d, J=10.4 Hz, 2H), 7.41 (d, J=7.2 Hz, 1H), 7.20 (d, J=7.6 1H),7.01 (dd, J=7.6, 6.6 Hz, 1H), 6.97 (dd, J=7.2, 6.8 Hz, 1H), 6.64 (d,J=15.6 Hz, 1H), 5.38 (s, 1H), 3.81-3.79 (m, 1H), 3.62-3.58 (m, 1H),3.50-3.46 (m, 1H), 3.31-3.10 (m, 4H), 2.74 (dd, J=18.4, 15.2 Hz, 1H),2.10-2.06 (m, 2H), 1.69-1.65 (m, 1H), 1.52-1.49 (m, 1H), 0.83 (t, J=7.2Hz, 3H), carboxylic acid proton not observed; MS (ESI) m/z 452.99[M+H]⁺.

(E)-3-(4-((1R,3R)-3-ethyl-2-((R)-tetrahydrofuran-3-yl)-2,3,4,9-tetrahydro-1H-pyrido[3,4-b]indol-1-yl)-3,5-difluorophenyl)acrylicacid: ¹H NMR (400 MHz, DMSO-d₆) δ 10.2 (s, 1H), 7.43-7.38 (m, 4H), 7.21(d, J=8.0, 1H), 7.01 (dd, J=7.6, 7.2 Hz, 1H), 6.95 (dd, J=7.2, 6.8 Hz,1H), 6.61 (d, J=16.4 Hz, 1H), 5.35 (s, 1H), 3.75-3.66 (m, 4H), 3.56-3.10(m, 1H), 3.08-3.00 (m, 1H), 2.76 (dd, J=17.8, 15.0 Hz, 1H), 2.69-2.58(m, 1H), 1.65-1.51 (m, 4H), 0.80 (t, J=7.2 Hz, 3H), carboxylic acidproton not observed; MS (ESI) m/z 452.96 [M+H]⁺.

Compounds 23A and 23B are shown above and in Table 1 with absolutestereochemistry in the tetrahydrofuran ring arbitrarily assigned.

Example 24(E)-3-(4-(2-(Bicyclo[1.1.1]pentan-1-ylmethyl)-3-ethyl-2,3,4,9-tetrahydro-1H-pyrido[3,4-b]indol-1-yl)-3,5-difluorophenyl)acrylicacid (24)

Step 1

To a stirred solution of 1-((1H-indol-3-yl)methyl)cyclopropanamine (0.19g, 1.02 mmol) in DCM (3.92 ml) were added HATU (0.312 g, 1.33 mmol) andN,N-diisopropylethylamine (0.355 ml, 2.04 mmol) at rt. The mixture wasstirred for 10 min and bicyclo[1.1.1]pentane-1-carboxylic acid (0.126 g,1.12 mmol) was added. After being stirred at rt for 16 h, the mixturewas diluted with ethyl acetate (15 mL) and washed with saturated aqueousNaHCO₃ solution. The organic layer was separated, dried over Na₂SO₄,filtered and concentrated. The resulting residue was purified by flashchromatography (SiO₂, 30-60% EtOAc in hexane) to affordN-(1-((1H-indol-3-yl)methyl)cyclopropyl)bicyclo[1.1.1]pentane-1-carboxamide(0.20 g, 0.713 mmol, 70% yield) as an off-white solid. MS (APCI) m/z281.16 [M+H]⁺.

Step 2

To a stirred solution ofN-(1-((1H-indol-3-yl)methyl)cyclopropyl)bicyclo[1.1.1]pentane-1-carboxamide(0.20 g, 0.713 mmol) in THF (2.85 ml) was added LAH (1.783 ml, 3.57mmol, 2M LAH in THF) dropwise at 0° C. After being refluxed for 18 h,the reaction mixture was quenched sequentially with cold (0-5° C.) water(0.15 mL), 15% aqueous NaOH (0.30 mL), and water (0.50 mL). Theresulting residue was extracted with EtOAc (3×10 mL). The combinedorganic layers were dried over Na₂SO₄, filtered, and concentrated. Theresulting residue was purified by flash chromatography (SiO₂, 0-50%DCM/(DCM:7M ammonia in MeOH (9:1 v/v))) to afford1-((1H-indol-3-yl)methyl)-N-(bicyclo[1.1.1]pentan-1-ylmethyl)cyclopropanamine(0.13 g, 68% yield) as a white solid. MS (APCI) m/z 267.18 [M+H]⁺.

Step 3

To a stirred solution of1-((1H-indol-3-yl)methyl)-N-(bicyclo[1.1.1]pentan-1-ylmethyl)cyclopropanamine(0.11 g, 0.413 mmol) in toluene (1.5 mL) were added (E)-ethyl3-(3,5-difluoro-4-formylphenyl)acrylate (0.11 g, 0.11 mmol) and aceticacid (0.050 g, 0.826 mmol) at 0° C. After being stirred at 80° C. for 3h, the reaction mixture was cooled to rt, diluted with EtOAc, and washedwith water. During the reaction, LCMS showed the formation of a sideproduct which corresponded to the rearrangement of the cyclopropyl ring.The organic layer was separated, dried over sodium sulfate, andconcentrated. The resulting residue was purified by flash chromatography(SiO₂, 0-20% EtOAc in hexane) to afford ethyl(E)-3-(4-(2-(bicyclo[1.1.1]pentan-1-ylmethyl)-3-ethyl-2,3,4,9-tetrahydro-1H-pyrido[3,4-b]indol-1-yl)-3,5-difluorophenyl)acrylate(0.10 g, 49% yield) as a mixture of isomers. MS (APCI) m/z 491.24[M+H]⁺.

Step 4

To a stirred solution of (E)-ethyl3-(4-(2-(bicyclo[1.1.1]pentan-1-ylmethyl)-3-ethyl-2,3,4,9-tetrahydro-1H-pyrido[3,4-b]indol-1-yl)-3,5-difluorophenyl)acrylate(0.10 g, 0.204 mmol) in a mixture of methanol (1 mL), THF (1 mL) andwater (1 mL) was added sodium hydroxide (0.024 g, 0.612 mmol) at 0° C.After being stirred at rt for 2 h, the organic solvents were removedunder reduced pressure and the resulting mixture was acidified withaqueous citric acid (1M) at 0° C. to adjust pH to 5. The formedprecipitate was extracted with EtOAc and the organic layer wasconcentrated. The resulting solid was dissolved in DMSO (1.5 mL) andpurified by reversed-phase HPLC using 10-50% acetonitrile (contains 0.1%formic acid) in water (contains 0.1% formic acid) to afford(E)-3-(4-(2-(bicyclo[1.1.1]pentan-1-ylmethyl)-3-ethyl-2,3,4,9-tetrahydro-1H-pyrido[3,4-b]indol-1-yl)-3,5-difluorophenyl)acrylicacid (0.03 g, 31% yield) as a mixture of isomers. MS (APCI) m/z 463.21[M+H]⁺.

Example 25A and 25B(E)-3-(4-((1R,3R)-2-(Bicyclo[1.1.1]pentan-1-yl)-3-ethyl-2,3,4,9-tetrahydro-1H-pyrido[3,4-b]indol-1-yl)-3,5-difluorophenyl)acrylicacid (25A)

(E)-3-(4-((1S,3S)-2-(Bicyclo[1.1.1]pentan-1-yl)-3-ethyl-2,3,4,9-tetrahydro-1H-pyrido[3,4-b]indol-1-yl)-3,5-difluorophenyl)acrylicacid (25B)

Step 1

To a stirred solution of 2-(1H-indol-3-yl)acetic acid (100 g, 571.4mmol) in dichloromethane (IL) was added 1,1-carbonyldiimidazole (92 g,571 mmol) in portions at rt under an argon atmosphere. The mixture wasstirred at rt for 2 h and N,O-dimethylhydroxylamine hydrochloride (54 g,571 mmol) was added. After being stirred at rt for 24 h, the reactionmixture was diluted with cold water and extracted with dichloromethane(2×250 mL). The combined organic layers were dried over sodium sulfate,filtered, and concentrated. The resultant residue was purified bytrituration with pentane to afford2-(1H-indol-3-yl)-N-methoxy-N-methylacetamide (110 g, 504.5 mmol, 80%yield) as an off white solid. MS (ESI) m/z; 218.84 [M+H]⁺.

Step 2

To a stirred solution of 2-(1H-indol-3-yl)-N-methoxy-N-methylacetamide(5.0 g, 22.9 mmol) in THF (350 mL) was added dropwise ethylmagnesiumbromide (22.5 mL, 67.6 mmol, 3M in diethyl ether) at 0° C. After beingstirred at 0° C. for another 2 h under an argon atmosphere, the reactionwas quenched by aqueous saturated NH₄Cl solution (200 mL) at 0° C. Theorganic layer was separated and the aqueous layer was extracted withEtOAc (2×200 mL). The combined organic layers were washed with water,brine, dried over sodium sulfate, filtered, and concentrated. The cruderesidue was purified by column chromatography (SiO₂, 30% ethyl acetatein hexanes) to afford 1-(1H-indol-3-yl)butan-2-one (2.78 g, 14.8 mmol,yield 60% yield) as an off white semi-solid. MS (ESI) m/z 188.15 [M+H]⁺.

Step 3

To a stirred solution of bicyclo[1.1.1]pentan-1-amine-HCl (0.9 g, 7.69mmol) in MeOH (180 mL) was added AcOH to adjust pH to 5-6. To themixture were added 1-(1H-Indol-3-yl)butan-2-one (1.2 g, 6.41 mmol) andsodium cyanoborohydride (720 mg, 11.5 mmol) at 0° C. After being stirredat rt for 12 h, the reaction mixture was concentrated under reducedpressure to remove organic solvents. The resultant residue was pouredinto water and extracted with EtOAc (2×100 mL). The combined organiclayer was washed with aqueous NaHCO₃ solution, water, and brine. Thewashed organic layer was then dried over sodium sulfate, filtered, andconcentrated. The residue was purified by column chromatography (SiO₂,30% ethyl acetate in hexanes) to affordN-(1-(1H-indol-3-yl)butan-2-yl)bicyclo[1.1.1]pentan-1-amine (0.90 g,3.54 mmol, 56% yield) as a yellow liquid. MS (ESI) m/z 255.0 [M+H]⁺.

Step 4

N-(1-(1H-indol-3-yl)butan-2-yl)bicyclo[1.1.1]pentan-1-amine (0.90 g) waspurified by Chiral SFC [Column: Lux Cellulose-2 (250×30 mm), 5 μm %CO₂:85.0: % Co solvent: 15.0% (0.5% DEA in MeOH): Total Flow: 90.0g/min: Back Pressure: 100.0 bar: UV: 219 nm: Stack time: 4.0 min:Load/Inj: 18.0 mg: Solubility: Methanol: No of injections: 50:Instrument details: Make/Model: Thar SFC-200-005] to afford(R)—N-(1-(1H-indol-3-yl)butan-2-yl)bicyclo[1.1.1]pentan-1-amine(Designated as Peak 1) (160 mg, 0.63 mmol, 32.0% yield) and(S)—N-(1-(1H-indol-3-yl)butan-2-yl)bicyclo[1.1.1]pentan-1-amine(Designated as Peak 2) (160 mg, 0.63 mmol, 33.0% yield) respectively.

(R)—N-(1-(1H-indol-3-yl)butan-2-yl)bicyclo[1.1.1]pentan-1-amine: MS(ESI) m/z 255.0 [M+H]⁺.

(S)—N-(1-(1H-indol-3-yl)butan-2-yl)bicyclo[1.1.1]pentan-1-amine: MS(ESI) m/z 255.0 [M+H]⁺.

Step 5-a

To a stirred solution of(R)—N-(1-(1H-indol-3-yl)butan-2-yl)bicyclo[1.1.1]pentan-1-amine (160 mg,0.63 mmol) in toluene (8.0 mL) were added(E)-methyl-3-(3,5-difluoro-4-formylphenyl) acrylate (142.0 mg, 0.63mmol) and AcOH (0.75 mL, 1.26 mmol) at 0° C. After being stirred at 90°C. for 6 h, the mixture was allowed to cool to rt, quenched by water,and extracted with ethyl acetate. The combined organic layer was driedover Na₂SO₄, filtered and concentrated. The residue was purified bycolumn chromatography (SiO₂, 20% ethyl acetate in hexane) to afford(E)-methyl3-(4-((1R,3R)-2-(bicyclo[1.1.1]pentan-1-yl)-3-ethyl-2,3,4,9-tetrahydro-1H-pyrido[3,4-b]indol-1-yl)-3,5-difluorophenyl)acrylate(120 mg, 0.26 mmol, 41% yield). MS (ESI) m/z 463.7 [M+H]⁺.

Step 5-b

To a stirred solution of(S)—N-(1-(1H-indol-3-yl)butan-2-yl)bicyclo[1.1.1]pentan-1-amine (160 mg,0.63 mmol) in toluene (8.0 mL) were added(E)-methyl-3-(3,5-difluoro-4-formylphenyl) acrylate (142.0 mg, 0.63mmol) and AcOH (0.75 mL, 1.26 mmol) at 0° C. After being stirred at 90°C. for 6 h, the reaction was cooled to rt, quenched by water, andextracted with ethyl acetate. The combined organic layer was dried overNa₂SO₄, filtered, and concentrated. The resultant residue was purifiedby column chromatography (SiO₂, 20% ethyl acetate in hexanes) to affordmethyl(E)-3-(4-((1S,3S)-2-(bicyclo[1.1.1]pentan-1-yl)-3-ethyl-2,3,4,9-tetrahydro-1H-pyrido[3,4-b]indol-1-yl)-3,5-difluorophenyl)acrylate(80 mg, 0.172 mmol, 27% yield). MS (ESI) m/z 463.7 [M+H]⁺.

Step 6-a

To a stirred solution of (E)-methyl3-(4-((1R,3R)-2-(bicyclo[1.1.1]pentan-1-yl)-3-ethyl-2,3,4,9-tetrahydro-1H-pyrido[3,4-b]indol-1-yl)-3,5-difluorophenyl)acrylate(120 mg, 0.26 mmol) in THF/water (5.0 mL, 1:1) was added LiOH (63 mg,1.56 mmol) at 0° C. After being stirred at rt for 6 h, the reactionmixture was washed with diethyl ether and the separated aqueous layerwas acidified to pH 3-4 with aqueous HCl (1.0M) at 0° C. The resultingprecipitate was filtered, washed with water, and dried to afford(E)-3-(4-((1R,3R)-2-(bicyclo[1.1.1]pentan-1-yl)-3-ethyl-2,3,4,9-tetrahydro-1H-pyrido[3,4-b]indol-1-yl)-3,5-difluorophenyl)acrylicacid (0.030 g, 0.0668 mmol, 26% yield) as a pale yellow solid. ¹H NMR(300 MHz, DMSO-d₆) δ 10.5 (br s, 1H), 7.57-7.40 (m, 4H), 7.19 (d, J=6.6Hz, 1H), 7.02-6.94 (m, 2H), 6.67 (d, J=15.6 Hz, 1H), 5.40 (s, 1H), 3.22(s, 1H), 2.78 (s, 2H), 2.26 (s, 1H), 1.78-1.66 (m, 6H), 1.40 (s, 1H),1.23 (s, 1H), 0.87-0.85 (m, 3H); mp: 178-180° C.; MS (ESI) m/z 449.11[M+H]⁺.

Step 6-b

To a stirred solution of(E)-methyl-3-(4-((1S,3S)-2-(bicyclo[1.1.1]pentan-1-yl)-3-ethyl-2,3,4,9-tetrahydro-1H-pyrido[3,4-b]indol-1-yl)-3,5-difluorophenyl)acrylicacid (80 mg, 0.173 mmol) in THF/water (5.0 mL, 1:1) was added LiOH (42mg, 1.03 mmol) at 0° C. After being stirred at rt for 6 h, the mixturewas washed with diethyl ether and the separated aqueous layer wasacidified to pH 3-4 with aqueous HCl (1.0M) at 0° C. The formedprecipitated was filtered, washed with water, and dried to afford(E)-3-(4-((1S,3S)-2-(bicyclo[1.1.1]pentan-1-yl)-3-ethyl-2,3,4,9-tetrahydro-1H-pyrido[3,4-b]indol-1-yl)-3,5-difluorophenyl)acrylicacid (0.011 g, 0.024 mmol, 14% yield) as a pale yellow solid. ¹H NMR(300 MHz, DMSO-d₆) δ 12.6 (br s, 1H), 10.6 (br s, 1H), 7.56-7.40 (m,4H), 7.18 (d, J=5.7 Hz, 1H), 7.00-6.92 (m, 2H), 6.66 (d, J=11.7 Hz, 1H),5.39 (s, 1H), 3.18 (s, 1H), 2.77 (s, 2H), 2.25 (s, 1H), 1.77-1.63 (m,6H), 1.43 (s, 1H), 1.23 (s, 1H), 0.85 (m, 3H); mp: 180-182° C.; MS (ESI)m/z 449.11 [M+H]⁺.

Compounds 25A and 25B are shown above and in Table 1 with absolutestereochemistry arbitrarily assigned.

Example 26A(E)-3-(4-((1R,3R)-2-(bicyclo[1.1.1]pentan-1-yl)-3,9-dimethyl-2,3,4,9-tetrahydro-1H-pyrido[3,4-b]indol-1-yl)-3,5-difluorophenyl)acrylicacid (26A)

Step 1

To a stirred solution of methyl(E)-3-(4-((1R,3R)-2-(bicyclo[1.1.1]pentan-1-yl)-3-methyl-2,3,4,9-tetrahydro-1H-pyrido[3,4-b]indol-1-yl)-3,5-difluorophenyl)acrylate(200 mg, 0.44 mmol) in dimethylcarbonate (2 mL) was added DABCO (5 mg,0.04 mmol) followed by DMF (0.2 mL, catalytic) at rt. After beingstirred at 95° C. for 40 h, the reaction mixture was quenched by coldwater and extracted with EtOAc (3×100 mL). The combined organic layerwas washed with water and brine. The washed organic layer was dried oversodium sulfate, filtered, and concentrated. The crude compound waspurified by flash chromatography (SiO₂ 25% ethyl acetate/hexanes) toafford methyl(E)-3-(4-((1R,3R)-2-(bicyclo[1.1.1]pentan-1-yl)-3,9-dimethyl-2,3,4,9-tetrahydro-1H-pyrido[3,4-b]indol-1-yl)-3,5-difluorophenyl)acrylate(80 mg, 0.17 mmol, 39% yield) as an off-white solid. MS (ESI) m/z 463.11[M+H]⁺.

Step 2

To a stirred solution of methyl(E)-3-(4-((1R,3R)-2-(bicyclo[1.1.1]pentan-1-yl)-3,9-dimethyl-2,3,4,9-tetrahydro-1H-pyrido[3,4-b]indol-1-yl)-3,5-difluorophenyl)acrylate(80 mg, 0.17 mmol) in THF/H₂O (1:1, total of 4 mL) was added LiOH.H₂O(130 mg, 0.51 mmol) at 0° C. After being stirred at rt for 5 h, thereaction mixture was concentrated under reduced pressure to remove theorganic solvent. The residue was acidified with 1N aqueous HCl at 0° C.and extracted with EtOAc (3×100 mL). The combined organic layer waswashed with water and brine, dried over sodium sulfate, filtered, andconcentrated. The crude compound was purified by flash chromatography(SiO₂, 2% MeOH/DCM) to afford(E)-3-(4-((1R,3R)-2-(bicyclo[1.1.1]pentan-1-yl)-3,9-dimethyl-2,3,4,9-tetrahydro-1H-pyrido[3,4-b]indol-1-yl)-3,5-difluorophenyl)acrylicacid (30 mg, 0.06 mmol, 38% yield). ¹H NMR (400 MHz, DMSO-d₆) δ 12.5 (brs, 1H), 7.52 (d, J=16.4 Hz, 2H), 7.44 (d, J=7.6 Hz, 2H), 7.31 (d, J=8.4Hz, 1H), 7.08 (t, J=7.2 Hz, 1H), 6.99 (t, J=7.2 Hz, 1H), 6.64 (d, J=16.0Hz, 1H), 5.44 (s, 1H), 3.50 (m, 1H), 3.33 (s, 3H), 2.91 (dd, J=14.4, 3.2Hz, 1H), 2.63 (m, 1H), 2.26 (s, 1H), 1.73 (d, J=9.6 Hz, 3H), 1.71 (d,J=8.8 Hz, 3H), 1.11 (d, J=6.4 Hz, 3H); MS (ESI) m/z 449.50 [M+1]+.

Example A Breast Cancer Cell Proliferation Assay (MCF-7)

MCF7 was expanded and maintained in the medium (Phenol red free DMEM/F12(Hyclone SH30272.01) NEAA (Gibco11140-050) Na-pyruvate (Gibco 11360-070)and Re-stripped Charcoal stripped FBS (Gemini 100-119)). The cells wereadjusted to a concentration of 3,000 cells per mL in the above media,and the cells were incubated (37° C., 5% CO₂). The following day a 10point, serial dilution of compounds was added to the cells at a finalconcentration ranging from 10-0.000005 μM for test compounds(17β-estradiol was used as a control). Additional cells were plated in30 wells to serve as the day 1 (pretreatment) comparison. After 5 daysof compound exposure, Cell Titer-Glo reagent was added to the cells andthe relative luminescence units (RLUs) of each well was determined. CellTiter-Glo was also added to 32 μL of medium without cells to obtain abackground value. The plates were allowed to incubate at roomtemperature for 10 minutes to stabilize luminescent signal and theluminescence signal was recorded with EnSpire. The relative increase incell number of each sample is determined as follows: (RLU sample-RLUbackground/RLU estrogen only treated cells-RLU background)×100=%inhibition.

Example B ER Degradation Determination by Western Blot

MCF-7 cells are plated at 0.3 million cells/mL (3 mL/well) in 6-wellplates in experiment media and incubated at 37° C., 5% CO2 for 48 hours.Next day, 10× solution of compounds are made in DMSO and added thesolution to the cells to achieve a final concentration of 10 μM. A DMSOcontrol is included to enable a determination of the relative efficacyof test compounds. Fulvestrant is used as a positive control forER-alpha degradation, and 4-OH tamoxifen as a control for receptorstabilization. After incubating cells with compounds for 18-24 hours,cell lysates are prepared (2× Cell lysis buffer:100 mM Tris, pH 8, 300mM NaCl, 2% NP40, 1% Na deoxycholate, 0.04% SDS, 2 mM EDTA) and mixedthoroughly and incubated on ice. The protein concentration is quantifiedusing BCA kit. Protein was separated on 4%-20% NuPAGE Novex 4-12%Bis-Tris Protein Gels using 1×MES running buffer. The gel was thentransferred onto a nitrocellulose membrane. The blots were probed withantibodies against ESR1 protein (Santa Cruz, sc-8005). GAPDH protein wasused as an internal control.

Example C ERα EC50 Determination

MCF-7 cells are plated at 0.3 million cells/mL (3 mL/well) in 6-wellplates in experiment media and incubated at 37° C., 5% CO2 for 48 hours.Next day, 10 mM solution of compounds are made in DMSO and added thesolution to the cells to achieve a final concentration of 10 μM. ForEC₅₀ determination, MCF-7 cells were incubated with 3× or 5× serialdilutions of 10 mM compounds, final concentration of the compounds wasfrom 10 μM to designed concentrations based on the potency of thecompounds. A DMSO control is included to enable a determination of therelative efficacy of test compounds. Fulvestrant is used as a positivecontrol for ER-alpha degradation, and 4-OH tamoxifen as a control forreceptor stabilization. After incubating cells with compounds for 18-24hours, cell lysates are prepared (2× Cell lysis buffer:100 mM Tris, pH8, 300 mM NaCl, 2% NP40, 1% Na deoxycholate, 0.04% SDS, 2 mM EDTA) andmixed thoroughly and incubated on ice. The protein concentration isquantified using BCA kit. Protein was separated on 4%-20% NuPAGE Novex4-12% Bis-Tris Protein Gels using 1×MES running buffer. The gel was thentransferred onto a nitrocellulose membrane. The blots were probed withantibodies against ESR1 protein (Santa Cruz, sc-8005). GAPDH protein wasused as an internal control. The blots were imaged on Azure C600 Imagerand Band density of the western blots was quantified with Azurespotsoftware. EC₅₀ is calculated with GraphpadPrism.

TABLE 3 MCF7 ERα % Example IC₅₀ (nM) degradation fulvestrant A A AZD9496A A ARN810 A A  4A B A  5A A A  6A ND B  8A B A  8B B B  9A B A 11A A A11C C ND 11D A ND 13A B ND 13B A B 14A B B 15A A ND 16A A ND 17A B ND18A A ND 19A A ND 21A A ND 22 B ND 23A A ND 23B B ND 24 B ND 25A C ND25B A ND 26A C ND For MCF7 IC₅₀: A = a single IC₅₀ ≤25 nM; B = a singleIC₅₀ ≥25 nM and ≤250 nM; C = a single IC₅₀ ≥250 nM. For ERα %degradation: A = ERα % degradation ≥80%; B = ERα % degradation <80%; ND= Not Determined.

Example D Pharmacokinetic Determination

Grouping female SD rats weighing 200-300 g randomly to two groups; onegroup was administered with test compound at a dose of 3.0 mg/kg byintravenous injection, the other group was administered with testcompound at a dose of 10.0 mg/kg by oral. The formulation for IV groupsis DMSO/PEG400/150 mM glycine (pH 9) (5/10/85) and the formulation forPO groups is PEG400/PVP/Tween 80/0.5% CMC in water (9/0.5/0.5/90). Afteradministering, blood samples of intravenous injection group werecollected at time points of predose, 0.0833, 0.25, 0.5, 1, 2, 4, 8, 12and 24 h; blood samples of oral group were collected at time points ofpredose, 0.25, 0.5, 1, 2, 4, 8, 12, and 24 h. Standard curve was plottedbased on concentrations of the samples in a suitable range, theconcentrations of test compounds in plasma samples were determined byusing LC-MS/MS. Pharmacokinetic parameters were calculated according todrug concentration-time curve using a noncompartmental method byWinNonLin (Phoenix™, version 6.1) or other similar software.

TABLE 4 Rat PK Dose AUC_(inf) Cl V_(dss) C_(max) T_(max) T_(1/2) FExample method (μM*h) (ml · min⁻¹ · kg⁻¹) (L/Kg) (μM) (h) (h) (%)AZD9496 IV 72 1.6 0.8 7.8 PO 179 16.1 4 6.4 74 ARN810 IV 5.9 19 1.2 4.7PO 23 6.7 1 6.9 117 5A IV 67 1.7 1.0 7.7 PO 185 10.8 2 8.5 82 8A IV 225.2 0.6 3.2 PO 80 24.5 0.5 2.1 109 11A  IV 96 1.2 0.48 4.2 PO 283 33 13.5 88

What is claimed is:
 1. A compound selected from the group consisting of


2. A compound of the following Formula 11-4:


3. A compound of the following Formula 11-5: